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Renaudin X, Campalans A. Modulation of OGG1 enzymatic activities by small molecules, promising tools and current challenges. DNA Repair (Amst) 2025; 149:103827. [PMID: 40120404 DOI: 10.1016/j.dnarep.2025.103827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/04/2025] [Accepted: 03/09/2025] [Indexed: 03/25/2025]
Abstract
Oxidative DNA damage, resulting from endogenous cellular processes and external sources plays a significant role in mutagenesis, cancer progression, and the pathogenesis of neurological disorders. Base Excision Repair (BER) is involved in the repair of base modifications such as oxidations or alkylations as well as single strand breaks. The DNA glycosylase OGG1, initiates the BER pathway by the recognition and excision of 8oxoG, the most common oxidative DNA lesion, in both nuclear and mitochondrial DNA. Beyond DNA repair, OGG1 modulates transcription, particularly pro-inflammatory genes, linking oxidative DNA damage to broader biological processes like inflammation and aging. In cancer therapy, BER inhibition has emerged as a promising strategy to enhance treatment efficacy. Targeting OGG1 sensitizes cells to chemotherapies, radiotherapies, and PARP inhibitors, presenting opportunities to overcome therapy resistance. Additionally, OGG1 activators hold potential in mitigating oxidative damage associated with aging and neurological disorders. This review presents the development of several inhibitors and activators of OGG1 and how they have contributed to advance our knowledge in the fundamental functions of OGG1. We also discuss the new opportunities they provide for clinical applications in treating cancer, inflammation and neurological disorders. Finally, we also highlight the challenges in targeting OGG1, particularly regarding the off-target effects recently reported for some inhibitors and how we can overcome these limitations.
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Affiliation(s)
- Xavier Renaudin
- Université Paris-Saclay, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France; Université Paris Cité, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France
| | - Anna Campalans
- Université Paris-Saclay, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France; Université Paris Cité, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France.
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2
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Shahi A, Kidane D. Decoding mitochondrial DNA damage and repair associated with H. pylori infection. Front Cell Infect Microbiol 2025; 14:1529441. [PMID: 39906209 PMCID: PMC11790445 DOI: 10.3389/fcimb.2024.1529441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Accepted: 12/19/2024] [Indexed: 02/06/2025] Open
Abstract
Mitochondrial genomic stability is critical to prevent various human inflammatory diseases. Bacterial infection significantly increases oxidative stress, driving mitochondrial genomic instability and initiating inflammatory human disease. Oxidative DNA base damage is predominantly repaired by base excision repair (BER) in the nucleus (nBER) as well as in the mitochondria (mtBER). In this review, we summarize the molecular mechanisms of spontaneous and H. pylori infection-associated oxidative mtDNA damage, mtDNA replication stress, and its impact on innate immune signaling. Additionally, we discuss how mutations located on mitochondria targeting sequence (MTS) of BER genes may contribute to mtDNA genome instability and innate immune signaling activation. Overall, the review summarizes evidence to understand the dynamics of mitochondria genome and the impact of mtBER in innate immune response during H. pylori-associated pathological outcomes.
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Affiliation(s)
| | - Dawit Kidane
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, United States
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3
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Vodicka P, Vodenkova S, Danesova N, Vodickova L, Zobalova R, Tomasova K, Boukalova S, Berridge MV, Neuzil J. Mitochondrial DNA damage, repair, and replacement in cancer. Trends Cancer 2025; 11:62-73. [PMID: 39438191 DOI: 10.1016/j.trecan.2024.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 09/24/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024]
Abstract
Mitochondria are vital organelles with their own DNA (mtDNA). mtDNA is circular and composed of heavy and light chains that are structurally more accessible than nuclear DNA (nDNA). While nDNA is typically diploid, the number of mtDNA copies per cell is higher and varies considerably during development and between tissues. Compared with nDNA, mtDNA is more prone to damage that is positively linked to many diseases, including cancer. Similar to nDNA, mtDNA undergoes repair processes, although these mechanisms are less well understood. In this review, we discuss the various forms of mtDNA damage and repair and their association with cancer initiation and progression. We also propose horizontal mitochondrial transfer as a novel mechanism for replacing damaged mtDNA.
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Affiliation(s)
- Pavel Vodicka
- Institute of Experimental Medicine, Czech Academy of Sciences, 142 20 Prague, Czech Republic; First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic.
| | - Sona Vodenkova
- Institute of Experimental Medicine, Czech Academy of Sciences, 142 20 Prague, Czech Republic; Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic.
| | - Natalie Danesova
- Institute of Experimental Medicine, Czech Academy of Sciences, 142 20 Prague, Czech Republic; Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
| | - Ludmila Vodickova
- Institute of Experimental Medicine, Czech Academy of Sciences, 142 20 Prague, Czech Republic; First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
| | - Renata Zobalova
- Institute of Biotechnology, Czech Academy of Sciences, 252 50 Prague-West, Czech Republic
| | - Kristyna Tomasova
- Institute of Experimental Medicine, Czech Academy of Sciences, 142 20 Prague, Czech Republic; Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
| | - Stepana Boukalova
- Institute of Biotechnology, Czech Academy of Sciences, 252 50 Prague-West, Czech Republic; Faculty of Science, Charles University, 128 00 Prague, Czech Republic
| | | | - Jiri Neuzil
- First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; Institute of Biotechnology, Czech Academy of Sciences, 252 50 Prague-West, Czech Republic; Faculty of Science, Charles University, 128 00 Prague, Czech Republic; School of Pharmacy and Medical Science, Griffith University, Southport, Qld 4222, Australia.
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4
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Neri S, Guidotti S, Panichi V, Minguzzi M, Cattini L, Platano D, Ursini F, Arciola CR, Borzì RM. IKKα affects the susceptibility of primary human osteoarthritis chondrocytes to oxidative stress-induced DNA damage by tuning autophagy. Free Radic Biol Med 2024; 225:726-740. [PMID: 39461484 DOI: 10.1016/j.freeradbiomed.2024.10.299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 10/29/2024]
Abstract
The functional derangement affecting human chondrocytes during osteoarthritis (OA) onset and progression is sustained by the failure of major homeostatic mechanisms. This makes them more susceptible to oxidative stress (OS), which can induce DNA damage responses and exacerbate stress-induced senescence. The knockdown (KD) of IκB kinase α (IKKα), a dispensable protein in healthy articular cartilage physiology, was shown to increase the survival and replication potential of human primary OA chondrocytes. Our recent findings showed that the DNA Mismatch Repair pathway only partially accounts for the reduced susceptibility to OS of IKKαKD cells. Here we therefore investigated other ROS-mediated DNA damage and repair mechanisms. We exposed IKKαWT and IKKαKD chondrocytes to sub-cytotoxic hydrogen peroxide and evaluated the occurrence of double-strand breaks (DSB), 8-oxo-2'-deoxyguanosine (8-oxo-dG) and telomere shortening. ROS exposure was able to significantly increase the number of γH2AX foci (directly related to the number of DSB) in both cell types, but IKKα deficient cells undergoing cell division were able to better recover compared to their IKKα proficient counterpart. 8-oxo-dG signal proved to be the highest DNA damage signal among those investigated, located in the mitochondria and with a slightly higher intensity in IKKα proficient cells immediately after OS exposure. Furthermore, ROS significantly reduced telomere length both in IKKαWT and IKKαKD, with the former showing more pervasive effects, especially in dividing cells. Assessment of the HIF-1α>Beclin-1>LC3B axis after recovery from OS showed that IKKα deficient cells exhibited a more efficient autophagic machinery that allowed them to better cope with oxidative stress, possibly through the turnover of damaged mitochondria. Higher Beclin-1 levels likely helped in rescuing dividing cells (identified by coupled cell cycle analysis) because of Beclin-1's involvement in both autophagy and mitotic spindle organization. Therefore, our data further confirm the higher capacity of IKKαKD chondrocytes to cope with oxidative stress-induced DNA damage.
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Affiliation(s)
- Simona Neri
- Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136, Bologna, Italy.
| | - Serena Guidotti
- Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136, Bologna, Italy.
| | - Veronica Panichi
- Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136, Bologna, Italy.
| | - Manuela Minguzzi
- Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136, Bologna, Italy.
| | - Luca Cattini
- Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136, Bologna, Italy.
| | - Daniela Platano
- Department of Biomedical and Neuromotor Sciences (DIBINEM), AlmaMater Studiorum University of Bologna, 40126, Bologna, Italy; Laboratory of Immunorheumatology and Tissue Regeneration, Physical Medicine and Rehabilitation Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
| | - Francesco Ursini
- Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136, Bologna, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM), AlmaMater Studiorum University of Bologna, 40126, Bologna, Italy.
| | - Carla Renata Arciola
- Laboratory of Immunorheumatology and Tissue Regeneration and Laboratory of Pathology of Implant Infections, IRCCS Istituto Ortopedico Rizzoli, 40136, Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), AlmaMater Studiorum University of Bologna, 40126, Bologna, Italy.
| | - Rosa Maria Borzì
- Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136, Bologna, Italy.
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Yuzefovych LV, Noh HL, Suk S, Schuler AM, Mulekar MS, Pastukh VM, Kim JK, Rachek LI. Mitochondria-Targeted DNA Repair Glycosylase hOGG1 Protects Against HFD-Induced Liver Oxidative Mitochondrial DNA Damage and Insulin Resistance in OGG1-Deficient Mice. Int J Mol Sci 2024; 25:12168. [PMID: 39596235 PMCID: PMC11595121 DOI: 10.3390/ijms252212168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/28/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
8-oxoguanine DNA glycosylase-1 (OGG1) is a DNA glycosylase mediating the first step in base excision repair which removes 7,8-dihydro-8-oxoguanine (8-oxoG) and repairs oxidized nuclear and mitochondrial DNA. Previous studies showed that OGG1 deficiency results in an increased susceptibility to high-fat diet (HFD)-induced obesity and metabolic dysfunction in mice, suggesting a crucial role of OGG1 in metabolism. However, the tissue-specific mechanisms of how OGG1 deficiency leads to insulin resistance is unknown. Thus, in the current study, we used a hyperinsulinemic-euglycemic clamp to evaluate in-depth glucose metabolism in male wild-type (WT) mice and Ogg1-/- (Ogg1-KO) mice fed an HFD. Ogg1-KO mice fed HFD were more obese, with significantly lower hepatic insulin action compared to WT/HFD mice. Targeting human OGG1 to mitochondria protected against HFD-induced obesity, insulin resistance, oxidative mitochondrial DNA damage in the liver and showed decreased expression of liver gluconeogenic genes in Ogg1-KO mice, suggesting a putative protective mechanism. Additionally, several subunits of oxidative phosphorylation protein levels were noticeably increased in Ogg1-KO/Tg compared to Ogg1-KO mice fed an HFD which was associated with improved insulin signaling. Our findings demonstrate the crucial role of mitochondrial hOGG1 in HFD-induced insulin resistance and propose several protective mechanisms which can further direct the development of therapeutic treatment.
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Affiliation(s)
- Larysa V. Yuzefovych
- Departments of Pharmacology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - Hye Lim Noh
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Sujin Suk
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Anne Michele Schuler
- Departments of Microbiology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - Madhuri S. Mulekar
- Department of Mathematics and Statistics, College of Art and Science, University of South Alabama, Mobile, AL 36688, USA
| | - Viktor M. Pastukh
- Departments of Pharmacology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - Jason K. Kim
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Lyudmila I. Rachek
- Departments of Pharmacology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA
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Tiwari A, Verma N, Shukla H, Mishra S, Kennedy K, Chatterjee T, Kuldeep J, Parwez S, Siddiqi MI, Ralph SA, Mishra S, Habib S. DNA N-glycosylases Ogg1 and EndoIII as components of base excision repair in Plasmodium falciparum organelles. Int J Parasitol 2024; 54:675-689. [PMID: 38964640 DOI: 10.1016/j.ijpara.2024.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/31/2024] [Accepted: 06/28/2024] [Indexed: 07/06/2024]
Abstract
The integrity of genomes of the two crucial organelles of the malaria parasite - an apicoplast and mitochondrion in each cell - must be maintained by DNA repair mediated by proteins targeted to these compartments. We explored the localisation and function of Plasmodium falciparum base excision repair (BER) DNA N-glycosylase homologs PfEndoIII and PfOgg1. These N-glycosylases would putatively recognise DNA lesions prior to the action of apurinic/apyrimidinic (AP)-endonucleases. Both Ape1 and Apn1 endonucleases have earlier been shown to function solely in the parasite mitochondrion. Immunofluorescence localisation showed that PfEndoIII was exclusively mitochondrial. PfOgg1 was not seen clearly in mitochondria when expressed as a PfOgg1leader-GFP fusion, although chromatin immunoprecipitation assays showed that it could interact with both mitochondrial and apicoplast DNA. Recombinant PfEndoIII functioned as a DNA N-glycosylase as well as an AP-lyase on thymine glycol (Tg) lesions. We further studied the importance of Ogg1 in the malaria life cycle using reverse genetic approaches in Plasmodium berghei. Targeted disruption of PbOgg1 resulted in loss of 8-oxo-G specific DNA glycosylase/lyase activity. PbOgg1 knockout did not affect blood, mosquito or liver stage development but caused reduced blood stage infection after inoculation of sporozoites in mice. A significant reduction in erythrocyte infectivity by PbOgg1 knockout hepatic merozoites was also observed, thus showing that PbOgg1 ensures smooth transition from liver to blood stage infection. Our results strengthen the view that the Plasmodium mitochondrial genome is an important site for DNA repair by the BER pathway.
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Affiliation(s)
- Anupama Tiwari
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Neetu Verma
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Himadri Shukla
- Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shivani Mishra
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Kit Kennedy
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
| | - Tribeni Chatterjee
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Jitendra Kuldeep
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shahid Parwez
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - M I Siddiqi
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Stuart A Ralph
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
| | - Satish Mishra
- Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| | - Saman Habib
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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7
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You Q, Feng X, Cai Y, Baylin SB, Li H. Human 8-oxoguanine glycosylase OGG1 binds nucleosome at the dsDNA ends and the super-helical locations. Commun Biol 2024; 7:1202. [PMID: 39341999 PMCID: PMC11438860 DOI: 10.1038/s42003-024-06919-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024] Open
Abstract
The human glycosylase OGG1 extrudes and excises the oxidized DNA base 8-oxoguanine (8-oxoG) to initiate base excision repair and plays important roles in many pathological conditions such as cancer, inflammation, and neurodegenerative diseases. Previous structural studies have used a truncated protein and short linear DNA, so it has been unclear how full-length OGG1 operates on longer DNA or on nucleosomes. Here we report cryo-EM structures of human OGG1 bound to a 35-bp long DNA containing an 8-oxoG within an unmethylated Cp-8-oxoG dinucleotide as well as to a nucleosome with an 8-oxoG at super-helical location (SHL)-5. The 8-oxoG in the linear DNA is flipped out by OGG1, consistent with previous crystallographic findings with a 15-bp DNA. OGG1 preferentially binds near dsDNA ends at the nucleosomal entry/exit sites. Such preference may underlie the enzyme's function in DNA double-strand break repair. Unexpectedly, we find that OGG1 bends the nucleosomal entry DNA, flips an undamaged guanine, and binds to internal nucleosomal DNA sites such as SHL-5 and SHL+6. We suggest that the DNA base search mechanism by OGG1 may be chromatin context-dependent and that OGG1 may partner with chromatin remodelers to excise 8-oxoG at the nucleosomal internal sites.
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Affiliation(s)
- Qinglong You
- Department of Structural Biology, Van Andel Institute, Grand Rapids, MI, USA
| | - Xiang Feng
- Department of Structural Biology, Van Andel Institute, Grand Rapids, MI, USA
| | - Yi Cai
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Stephen B Baylin
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
| | - Huilin Li
- Department of Structural Biology, Van Andel Institute, Grand Rapids, MI, USA.
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Sharma P, Wong CP, Ho E, Sampath H. Catalytic activity of OGG1 is impaired by Zinc deficiency. DNA Repair (Amst) 2024; 134:103628. [PMID: 38228016 PMCID: PMC10851324 DOI: 10.1016/j.dnarep.2024.103628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 12/15/2023] [Accepted: 01/03/2024] [Indexed: 01/18/2024]
Abstract
Oxidative stress-induced DNA base modifications, if unrepaired, can increase mutagenesis and genomic instability, ultimately leading to cell death. Cells predominantly use the base excision repair (BER) pathway to repair oxidatively-induced non-helix distorting lesions. BER is initiated by DNA glycosylases, such as 8-oxoguanine DNA glycosylase (OGG1), which repairs oxidatively modified guanine bases, including 7,8-dihydro-8-oxoguanine (8-oxoG) and ring-opened formamidopyrimidine lesions, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG). The OGG1 protein contains a C2H2 zinc (Zn) finger DNA binding domain. However, the impact of dietary Zn deficiency on OGG1 catalytic activity has not been extensively studied. Zn is a common nutrient of concern with increasing age, and the prevalence of oxidative DNA damage is also concurrently increased during aging. Thus, understanding the potential regulation of OGG1 activity by Zn is clinically relevant. The present study investigates the impact of a range of Zn statuses, varying from severe Zn deficiency to exogenous Zn-supplementation, in the context of young and aged animals to determine the impact of dietary Zn-status on OGG1 activity and oxidative DNA damage in mice. Our findings suggest that nutritional Zn deficiency impairs OGG1 activity and function, without altering gene expression, and that aging further exacerbates these effects. These results have important implications for nutritional management of Zn during aging to mitigate age-associated DNA damage.
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Affiliation(s)
- Priyanka Sharma
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USA; Center for Microbiome, Nutrition, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, USA; Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Carmen P Wong
- Linus Pauling Institute, Oregon State University, Corvallis, OR, USA; School of Public Health and Nutrition, Oregon State University, Corvallis, OR, USA
| | - Emily Ho
- Linus Pauling Institute, Oregon State University, Corvallis, OR, USA; School of Public Health and Nutrition, Oregon State University, Corvallis, OR, USA
| | - Harini Sampath
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USA; Center for Microbiome, Nutrition, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, USA; Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA.
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9
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Scala G, Ambrosio S, Menna M, Gorini F, Caiazza C, Cooke MS, Majello B, Amente S. Accumulation of 8-oxodG within the human mitochondrial genome positively associates with transcription. NAR Genom Bioinform 2023; 5:lqad100. [PMID: 37954575 PMCID: PMC10632194 DOI: 10.1093/nargab/lqad100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/14/2023] Open
Abstract
Mitochondrial DNA (mtDNA) can be subject to internal and environmental stressors that lead to oxidatively generated damage and the formation of 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxodG). The accumulation of 8-oxodG has been linked to degenerative diseases and aging, as well as cancer. Despite the well-described implications of 8-oxodG in mtDNA for mitochondrial function, there have been no reports of mapping of 8-oxodG across the mitochondrial genome. To address this, we used OxiDIP-Seq and mapped 8-oxodG levels in the mitochondrial genome of human MCF10A cells. Our findings indicated that, under steady-state conditions, 8-oxodG is non-uniformly distributed along the mitochondrial genome, and that the longer non-coding region appeared to be more protected from 8-oxodG accumulation compared with the coding region. However, when the cells have been exposed to oxidative stress, 8-oxodG preferentially accumulated in the coding region which is highly transcribed as H1 transcript. Our data suggest that 8-oxodG accumulation in the mitochondrial genome is positively associated with mitochondrial transcription.
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Affiliation(s)
- Giovanni Scala
- Department of Biology, University of Naples Federico II, 80138 Naples, Italy
| | - Susanna Ambrosio
- Department of Biology, University of Naples Federico II, 80138 Naples, Italy
| | - Margherita Menna
- Department of Biology, University of Naples Federico II, 80138 Naples, Italy
| | - Francesca Gorini
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy
| | - Carmen Caiazza
- Department of Biology, University of Naples Federico II, 80138 Naples, Italy
| | - Marcus S Cooke
- Oxidative Stress Group, Department of Molecular Biosciences, University of South Florida, Tampa, FL 33620, USA
| | - Barbara Majello
- Department of Biology, University of Naples Federico II, 80138 Naples, Italy
| | - Stefano Amente
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy
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Darbinian N, Darbinyan A, Merabova N, Kassem M, Tatevosian G, Amini S, Goetzl L, Selzer ME. In utero ethanol exposure induces mitochondrial DNA damage and inhibits mtDNA repair in developing brain. Front Neurosci 2023; 17:1214958. [PMID: 37621718 PMCID: PMC10444992 DOI: 10.3389/fnins.2023.1214958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 07/24/2023] [Indexed: 08/26/2023] Open
Abstract
Introduction Mitochondrial dysfunction is postulated to be a central event in fetal alcohol spectrum disorders (FASD). People with the most severe form of FASD, fetal alcohol syndrome (FAS) are estimated to live only 34 years (95% confidence interval, 31 to 37 years), and adults who were born with any form of FASD often develop early aging. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage, hallmarks of aging, are postulated central events in FASD. Ethanol (EtOH) can cause mtDNA damage, consequent increased oxidative stress, and changes in the mtDNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1). Studies of molecular mechanisms are limited by the absence of suitable human models and non-invasive tools. Methods We compared human and rat EtOH-exposed fetal brain tissues and neuronal cultures, and fetal brain-derived exosomes (FB-Es) from maternal blood. Rat FASD was induced by administering a 6.7% alcohol liquid diet to pregnant dams. Human fetal (11-21 weeks) brain tissue was collected and characterized by maternal self-reported EtOH use. mtDNA was amplified by qPCR. OGG1 and Insulin-like growth factor 1 (IGF-1) mRNAs were assayed by qRT-PCR. Exosomal OGG1 was measured by ddPCR. Results Maternal EtOH exposure increased mtDNA damage in fetal brain tissue and FB-Es. The damaged mtDNA in FB-Es correlated highly with small eye diameter, an anatomical hallmark of FASD. OGG1-mediated mtDNA repair was inhibited in EtOH-exposed fetal brain tissues. IGF-1 rescued neurons from EtOH-mediated mtDNA damage and OGG1 inhibition. Conclusion The correlation between mtDNA damage and small eye size suggests that the amount of damaged mtDNA in FB-E may serve as a marker to predict which at risk fetuses will be born with FASD. Moreover, IGF-1 might reduce EtOH-caused mtDNA damage and neuronal apoptosis.
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Affiliation(s)
- Nune Darbinian
- Center for Neural Repair and Rehabilitation (Shriners Hospitals Pediatric Research Center), Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Armine Darbinyan
- Department of Pathology, Yale University School of Medicine, New Haven, CT, United States
| | - Nana Merabova
- Center for Neural Repair and Rehabilitation (Shriners Hospitals Pediatric Research Center), Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- Medical College of Wisconsin-Prevea Health, Green Bay, WI, United States
| | - Myrna Kassem
- Center for Neural Repair and Rehabilitation (Shriners Hospitals Pediatric Research Center), Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, United States
| | - Gabriel Tatevosian
- Center for Neural Repair and Rehabilitation (Shriners Hospitals Pediatric Research Center), Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Shohreh Amini
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, United States
| | - Laura Goetzl
- Department of Obstetrics and Gynecology, University of Texas, Houston, TX, United States
| | - Michael E. Selzer
- Center for Neural Repair and Rehabilitation (Shriners Hospitals Pediatric Research Center), Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
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Hussain M, Chu X, Duan Sahbaz B, Gray S, Pekhale K, Park JH, Croteau DL, Bohr VA. Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA. Free Radic Biol Med 2023; 203:34-44. [PMID: 37011700 PMCID: PMC10247526 DOI: 10.1016/j.freeradbiomed.2023.03.262] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/15/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023]
Abstract
Aging is accompanied by a decline in DNA repair efficiency, which leads to the accumulation of different types of DNA damage. Age-associated chronic inflammation and generation of reactive oxygen species exacerbate the aging process and age-related chronic disorders. These inflammatory processes establish conditions that favor accumulation of DNA base damage, especially 8-oxo-7,8 di-hydroguanine (8-oxoG), which in turn contributes to various age associated diseases. 8-oxoG is repaired by 8-oxoG glycosylase1 (OGG1) through the base excision repair (BER) pathway. OGG1 is present in both the cell nucleus and in mitochondria. Mitochondrial OGG1 has been implicated in mitochondrial DNA repair and increased mitochondrial function. Using transgenic mouse models and cell lines that have been engineered to have enhanced expression of mitochondria-targeted OGG1 (mtOGG1), we show that elevated levels of mtOGG1 in mitochondria can reverse aging-associated inflammation and improve functions. Old male mtOGG1Tg mice show decreased inflammation response, decreased TNFα levels and multiple pro-inflammatory cytokines. Moreover, we observe that male mtOGG1Tg mice show resistance to STING activation. Interestingly, female mtOGG1Tg mice did not respond to mtOGG1 overexpression. Further, HMC3 cells expressing mtOGG1 display decreased release of mtDNA into the cytoplasm after lipopolysacchride induction and regulate inflammation through the pSTING pathway. Also, increased mtOGG1 expression reduced LPS-induced loss of mitochondrial functions. These results suggest that mtOGG1 regulates age-associated inflammation by controlling release of mtDNA into the cytoplasm.
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Affiliation(s)
- Mansoor Hussain
- DNA repair section, National Institute on Aging, Baltimore, MD, 21224, USA
| | - Xixia Chu
- DNA repair section, National Institute on Aging, Baltimore, MD, 21224, USA
| | - Burcin Duan Sahbaz
- DNA repair section, National Institute on Aging, Baltimore, MD, 21224, USA
| | - Samuel Gray
- DNA repair section, National Institute on Aging, Baltimore, MD, 21224, USA
| | - Komal Pekhale
- DNA repair section, National Institute on Aging, Baltimore, MD, 21224, USA
| | - Jae-Hyeon Park
- DNA repair section, National Institute on Aging, Baltimore, MD, 21224, USA
| | - Deborah L Croteau
- DNA repair section, National Institute on Aging, Baltimore, MD, 21224, USA; Computational Biology & Genomics Core, National Institute on Aging, Baltimore, MD, 21224, USA
| | - Vilhelm A Bohr
- DNA repair section, National Institute on Aging, Baltimore, MD, 21224, USA; Danish Center for Healthy Aging, University of Copenhagen, Copenhagen, 2200, Denmark.
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12
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Tsirkas I, Zur T, Dovrat D, Cohen A, Ravkaie L, Aharoni A. Protein fluorescent labeling in live yeast cells using scFv-based probes. CELL REPORTS METHODS 2022; 2:100357. [PMID: 36590693 PMCID: PMC9795370 DOI: 10.1016/j.crmeth.2022.100357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 09/19/2022] [Accepted: 11/10/2022] [Indexed: 12/12/2022]
Abstract
The fusion of fluorescent proteins (FPs) to endogenous proteins is a widespread approach for microscopic examination of protein function, expression, and localization in the cell. However, proteins that are sensitive to FP fusion or expressed at low levels are difficult to monitor using this approach. Here, we develop a single-chain fragment variable (scFv)-FP approach to efficiently label Saccharomyces cerevisiae proteins that are tagged with repeats of hemagglutinin (HA)-tag sequences. We demonstrate the successful labeling of DNA-binding proteins and proteins localized to different cellular organelles including the nuclear membrane, peroxisome, Golgi apparatus, and mitochondria. This approach can lead to a significant increase in fluorescence intensity of the labeled protein, allows C'-terminal labeling of difficult-to-tag proteins and increased detection sensitivity of DNA-damage foci. Overall, the development of a scFv-FP labeling approach in yeast provides a general and simple tool for the function and localization analysis of the yeast proteome.
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Affiliation(s)
- Ioannis Tsirkas
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be’er Sheva 84105, Israel
| | - Tomer Zur
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be’er Sheva 84105, Israel
| | - Daniel Dovrat
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be’er Sheva 84105, Israel
| | - Amit Cohen
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be’er Sheva 84105, Israel
| | - Lior Ravkaie
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be’er Sheva 84105, Israel
| | - Amir Aharoni
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be’er Sheva 84105, Israel
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Akbari M, Nilsen HL, Montaldo NP. Dynamic features of human mitochondrial DNA maintenance and transcription. Front Cell Dev Biol 2022; 10:984245. [PMID: 36158192 PMCID: PMC9491825 DOI: 10.3389/fcell.2022.984245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/02/2022] [Indexed: 12/03/2022] Open
Abstract
Mitochondria are the primary sites for cellular energy production and are required for many essential cellular processes. Mitochondrial DNA (mtDNA) is a 16.6 kb circular DNA molecule that encodes only 13 gene products of the approximately 90 different proteins of the respiratory chain complexes and an estimated 1,200 mitochondrial proteins. MtDNA is, however, crucial for organismal development, normal function, and survival. MtDNA maintenance requires mitochondrially targeted nuclear DNA repair enzymes, a mtDNA replisome that is unique to mitochondria, and systems that control mitochondrial morphology and quality control. Here, we provide an overview of the current literature on mtDNA repair and transcription machineries and discuss how dynamic functional interactions between the components of these systems regulate mtDNA maintenance and transcription. A profound understanding of the molecular mechanisms that control mtDNA maintenance and transcription is important as loss of mtDNA integrity is implicated in normal process of aging, inflammation, and the etiology and pathogenesis of a number of diseases.
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Affiliation(s)
- Mansour Akbari
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Hilde Loge Nilsen
- Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Unit for precision medicine, Akershus University Hospital, Nordbyhagen, Norway
- Department of Microbiology, Oslo University Hospital, Oslo, Norway
| | - Nicola Pietro Montaldo
- Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- *Correspondence: Nicola Pietro Montaldo,
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14
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Torgasheva NA, Diatlova EA, Grin IR, Endutkin AV, Mechetin GV, Vokhtantsev IP, Yudkina AV, Zharkov DO. Noncatalytic Domains in DNA Glycosylases. Int J Mol Sci 2022; 23:ijms23137286. [PMID: 35806289 PMCID: PMC9266487 DOI: 10.3390/ijms23137286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 02/04/2023] Open
Abstract
Many proteins consist of two or more structural domains: separate parts that have a defined structure and function. For example, in enzymes, the catalytic activity is often localized in a core fragment, while other domains or disordered parts of the same protein participate in a number of regulatory processes. This situation is often observed in many DNA glycosylases, the proteins that remove damaged nucleobases thus initiating base excision DNA repair. This review covers the present knowledge about the functions and evolution of such noncatalytic parts in DNA glycosylases, mostly concerned with the human enzymes but also considering some unique members of this group coming from plants and prokaryotes.
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Affiliation(s)
- Natalia A. Torgasheva
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Avenue, 630090 Novosibirsk, Russia; (N.A.T.); (E.A.D.); (I.R.G.); (A.V.E.); (G.V.M.); (I.P.V.); (A.V.Y.)
| | - Evgeniia A. Diatlova
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Avenue, 630090 Novosibirsk, Russia; (N.A.T.); (E.A.D.); (I.R.G.); (A.V.E.); (G.V.M.); (I.P.V.); (A.V.Y.)
- Department of Natural Sciences, Novosibirsk State University, 2 Pirogova Street, 630090 Novosibirsk, Russia
| | - Inga R. Grin
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Avenue, 630090 Novosibirsk, Russia; (N.A.T.); (E.A.D.); (I.R.G.); (A.V.E.); (G.V.M.); (I.P.V.); (A.V.Y.)
| | - Anton V. Endutkin
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Avenue, 630090 Novosibirsk, Russia; (N.A.T.); (E.A.D.); (I.R.G.); (A.V.E.); (G.V.M.); (I.P.V.); (A.V.Y.)
| | - Grigory V. Mechetin
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Avenue, 630090 Novosibirsk, Russia; (N.A.T.); (E.A.D.); (I.R.G.); (A.V.E.); (G.V.M.); (I.P.V.); (A.V.Y.)
| | - Ivan P. Vokhtantsev
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Avenue, 630090 Novosibirsk, Russia; (N.A.T.); (E.A.D.); (I.R.G.); (A.V.E.); (G.V.M.); (I.P.V.); (A.V.Y.)
- Department of Natural Sciences, Novosibirsk State University, 2 Pirogova Street, 630090 Novosibirsk, Russia
| | - Anna V. Yudkina
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Avenue, 630090 Novosibirsk, Russia; (N.A.T.); (E.A.D.); (I.R.G.); (A.V.E.); (G.V.M.); (I.P.V.); (A.V.Y.)
| | - Dmitry O. Zharkov
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Avenue, 630090 Novosibirsk, Russia; (N.A.T.); (E.A.D.); (I.R.G.); (A.V.E.); (G.V.M.); (I.P.V.); (A.V.Y.)
- Department of Natural Sciences, Novosibirsk State University, 2 Pirogova Street, 630090 Novosibirsk, Russia
- Correspondence:
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15
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Li X, Cao G, Liu X, Tang TS, Guo C, Liu H. Polymerases and DNA Repair in Neurons: Implications in Neuronal Survival and Neurodegenerative Diseases. Front Cell Neurosci 2022; 16:852002. [PMID: 35846567 PMCID: PMC9279898 DOI: 10.3389/fncel.2022.852002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 05/23/2022] [Indexed: 12/22/2022] Open
Abstract
Most of the neurodegenerative diseases and aging are associated with reactive oxygen species (ROS) or other intracellular damaging agents that challenge the genome integrity of the neurons. As most of the mature neurons stay in G0/G1 phase, replication-uncoupled DNA repair pathways including BER, NER, SSBR, and NHEJ, are pivotal, efficient, and economic mechanisms to maintain genomic stability without reactivating cell cycle. In these progresses, polymerases are prominent, not only because they are responsible for both sensing and repairing damages, but also for their more diversified roles depending on the cell cycle phase and damage types. In this review, we summarized recent knowledge on the structural and biochemical properties of distinct polymerases, including DNA and RNA polymerases, which are known to be expressed and active in nervous system; the biological relevance of these polymerases and their interactors with neuronal degeneration would be most graphically illustrated by the neurological abnormalities observed in patients with hereditary diseases associated with defects in DNA repair; furthermore, the vicious cycle of the trinucleotide repeat (TNR) and impaired DNA repair pathway is also discussed. Unraveling the mechanisms and contextual basis of the role of the polymerases in DNA damage response and repair will promote our understanding about how long-lived postmitotic cells cope with DNA lesions, and why disrupted DNA repair contributes to disease origin, despite the diversity of mutations in genes. This knowledge may lead to new insight into the development of targeted intervention for neurodegenerative diseases.
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Affiliation(s)
- Xiaoling Li
- Nano-Biotechnology Key Lab of Hebei Province, Yanshan University, Qinhuangdao, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
- Xiaoling Li
| | - Guanghui Cao
- Nano-Biotechnology Key Lab of Hebei Province, Yanshan University, Qinhuangdao, China
| | - Xiaokang Liu
- Nano-Biotechnology Key Lab of Hebei Province, Yanshan University, Qinhuangdao, China
| | - Tie-Shan Tang
- State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Caixia Guo
- Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China
- *Correspondence: Caixia Guo
| | - Hongmei Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Hongmei Liu
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16
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Roy A, Kandettu A, Ray S, Chakrabarty S. Mitochondrial DNA replication and repair defects: Clinical phenotypes and therapeutic interventions. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2022; 1863:148554. [PMID: 35341749 DOI: 10.1016/j.bbabio.2022.148554] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/06/2022] [Accepted: 03/16/2022] [Indexed: 12/15/2022]
Abstract
Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle contains its circular genome - mtDNA (mitochondrial DNA), that undergoes continuous cycles of replication and repair to maintain the mitochondrial genome integrity. The majority of the mitochondrial genes, including mitochondrial replisome and repair genes, are nuclear-encoded. Although the repair machinery of mitochondria is quite efficient, the mitochondrial genome is highly susceptible to oxidative damage and other types of exogenous and endogenous agent-induced DNA damage, due to the absence of protective histones and their proximity to the main ROS production sites. Mutations in replication and repair genes of mitochondria can result in mtDNA depletion and deletions subsequently leading to mitochondrial genome instability. The combined action of mutations and deletions can result in compromised mitochondrial genome maintenance and lead to various mitochondrial disorders. Here, we review the mechanism of mitochondrial DNA replication and repair process, key proteins involved, and their altered function in mitochondrial disorders. The focus of this review will be on the key genes of mitochondrial DNA replication and repair machinery and the clinical phenotypes associated with mutations in these genes.
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Affiliation(s)
- Abhipsa Roy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Amoolya Kandettu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Swagat Ray
- Department of Life Sciences, School of Life and Environmental Sciences, University of Lincoln, Lincoln LN6 7TS, United Kingdom
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
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17
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Cecchini NM, Torres JR, López IL, Cobo S, Nota F, Alvarez ME. Alternative splicing of an exitron determines the subnuclear localization of the Arabidopsis DNA glycosylase MBD4L under heat stress. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2022; 110:377-388. [PMID: 35061303 DOI: 10.1111/tpj.15675] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 01/15/2022] [Indexed: 06/14/2023]
Affiliation(s)
- Nicolás Miguel Cecchini
- Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC, CONICET, Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba, Argentina
| | - José Roberto Torres
- Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC, CONICET, Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba, Argentina
| | - Ignacio Lescano López
- Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC, CONICET, Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba, Argentina
| | - Santiago Cobo
- Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC, CONICET, Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba, Argentina
| | - Florencia Nota
- Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC, CONICET, Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba, Argentina
| | - María Elena Alvarez
- Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC, CONICET, Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba, Argentina
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18
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MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8635088. [PMID: 34970419 PMCID: PMC8714343 DOI: 10.1155/2021/8635088] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 10/29/2021] [Accepted: 11/19/2021] [Indexed: 12/12/2022]
Abstract
Oxidative stress is a major risk factor for Alzheimer's disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into App NL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in App NL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.
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19
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Mizuno Y, Abolhassani N, Mazzei G, Saito T, Saido TC, Yamasaki R, Kira JI, Nakabeppu Y. Deficiency of MTH1 and/or OGG1 increases the accumulation of 8-oxoguanine in the brain of the App NL-G-F/NL-G-F knock-in mouse model of Alzheimer's disease, accompanied by accelerated microgliosis and reduced anxiety-like behavior. Neurosci Res 2021; 177:118-134. [PMID: 34838904 DOI: 10.1016/j.neures.2021.11.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 11/12/2021] [Accepted: 11/24/2021] [Indexed: 11/24/2022]
Abstract
Oxidative stress is a major risk factor for Alzheimer's disease (AD). Among various oxidized molecules, the marked accumulation of an oxidized form of guanine, 8-oxo-7,8-dihydroguanine (8-oxoG), is observed in the AD brain. 8-oxo-2'-deoxyguanosine triphosphatase (MTH1) and 8-oxoG DNA glycosylase (OGG1) minimize the 8-oxoG accumulation in DNA, and their expression is decreased in the AD brain. MTH1 and/or OGG1 may suppress the pathogenesis of AD; however, their exact roles remain unclear. We evaluated the roles of MTH1 and OGG1 during the pathogenesis of AD using AppNL-G-F/NL-G-F knock-in mice (a preclinical AD model). Six-month-old female AppNL-G-F/NL-G-F mice with MTH1 and/or OGG1 deficiency exhibited reduced anxiety-related behavior, but their cognitive and locomotive functions were unchanged; the alteration was less evident in 12-month-old mice. MTH1 and/or OGG1 deficiency accelerated the 8-oxoG accumulation and microgliosis in the amygdala and cortex of six-month-old mice; the alteration was less evident in 12-month-old mice. Astrocytes and neurons were not influenced. We showed that MTH1 and OGG1 are essential for minimizing oxidative DNA damage in the AppNL-G-F/NL-G-F brain, and the effects are age-dependent. MTH1 and/or OGG1 deficiency reduced anxiety-related behavior in AppNL-G-F/NL-G-F mice with a significant acceleration of the 8-oxoG burden and microgliosis, especially in the cortex and amygdala.
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Affiliation(s)
- Yuri Mizuno
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Nona Abolhassani
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Guianfranco Mazzei
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takashi Saito
- Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan
| | - Takaomi C Saido
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan
| | - Ryo Yamasaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Jun-Ichi Kira
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Translational Neuroscience Center, Graduate School of Medicine, School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, Fukuoka, 831-8501, Japan
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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Jurcau A. Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress. Int J Mol Sci 2021; 22:11847. [PMID: 34769277 PMCID: PMC8584731 DOI: 10.3390/ijms222111847] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 10/25/2021] [Accepted: 10/28/2021] [Indexed: 12/12/2022] Open
Abstract
As the population ages, the incidence of neurodegenerative diseases is increasing. Due to intensive research, important steps in the elucidation of pathogenetic cascades have been made and significantly implicated mitochondrial dysfunction and oxidative stress. However, the available treatment in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis is mainly symptomatic, providing minor benefits and, at most, slowing down the progression of the disease. Although in preclinical setting, drugs targeting mitochondrial dysfunction and oxidative stress yielded encouraging results, clinical trials failed or had inconclusive results. It is likely that by the time of clinical diagnosis, the pathogenetic cascades are full-blown and significant numbers of neurons have already degenerated, making it impossible for mitochondria-targeted or antioxidant molecules to stop or reverse the process. Until further research will provide more efficient molecules, a healthy lifestyle, with plenty of dietary antioxidants and avoidance of exogenous oxidants may postpone the onset of neurodegeneration, while familial cases may benefit from genetic testing and aggressive therapy started in the preclinical stage.
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Affiliation(s)
- Anamaria Jurcau
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
- Neurology Ward, Clinical Municipal Hospital “dr. G. Curteanu” Oradea, 410154 Oradea, Romania
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21
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Allkanjari K, Baldock RA. Beyond base excision repair: an evolving picture of mitochondrial DNA repair. Biosci Rep 2021; 41:BSR20211320. [PMID: 34608928 PMCID: PMC8527207 DOI: 10.1042/bsr20211320] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/29/2021] [Accepted: 10/04/2021] [Indexed: 12/11/2022] Open
Abstract
Mitochondria are highly specialised organelles required for key cellular processes including ATP production through cellular respiration and controlling cell death via apoptosis. Unlike other organelles, mitochondria contain their own DNA genome which encodes both protein and RNA required for cellular respiration. Each cell may contain hundreds to thousands of copies of the mitochondrial genome, which is essential for normal cellular function - deviation of mitochondrial DNA (mtDNA) copy number is associated with cellular ageing and disease. Furthermore, mtDNA lesions can arise from both endogenous or exogenous sources and must either be tolerated or corrected to preserve mitochondrial function. Importantly, replication of damaged mtDNA can lead to stalling and introduction of mutations or genetic loss, mitochondria have adapted mechanisms to repair damaged DNA. These mechanisms rely on nuclear-encoded DNA repair proteins that are translocated into the mitochondria. Despite the presence of many known nuclear DNA repair proteins being found in the mitochondrial proteome, it remains to be established which DNA repair mechanisms are functional in mammalian mitochondria. Here, we summarise the existing and emerging research, alongside examining proteomic evidence, demonstrating that mtDNA damage can be repaired using Base Excision Repair (BER), Homologous Recombination (HR) and Microhomology-mediated End Joining (MMEJ). Critically, these repair mechanisms do not operate in isolation and evidence for interplay between pathways and repair associated with replication is discussed. Importantly, characterising non-canonical functions of key proteins and understanding the bespoke pathways used to tolerate, repair or bypass DNA damage will be fundamental in fully understanding the causes of mitochondrial genome mutations and mitochondrial dysfunction.
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Affiliation(s)
- Kathrin Allkanjari
- Formerly: Solent University Southampton, East Park Terrace, Southampton, SO14 0YN, UK
| | - Robert A. Baldock
- School of Natural and Social Sciences, University of Gloucestershire, Francis Close Hall, Swindon Road, Cheltenham GL50 4AZ, UK
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22
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Nakamura T, Okabe K, Hirayama S, Chirifu M, Ikemizu S, Morioka H, Nakabeppu Y, Yamagata Y. Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer. Nucleic Acids Res 2021; 49:7154-7163. [PMID: 34142156 PMCID: PMC8266592 DOI: 10.1093/nar/gkab492] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/17/2021] [Accepted: 05/22/2021] [Indexed: 11/17/2022] Open
Abstract
Mammalian MutY homologue (MUTYH) is an adenine DNA glycosylase that excises adenine inserted opposite 8-oxoguanine (8-oxoG). The inherited variations in human MUTYH gene are known to cause MUTYH-associated polyposis (MAP), which is associated with colorectal cancer. MUTYH is involved in base excision repair (BER) with proliferating cell nuclear antigen (PCNA) in DNA replication, which is unique and critical for effective mutation-avoidance. It is also reported that MUTYH has a Zn-binding motif in a unique interdomain connector (IDC) region, which interacts with Rad9–Rad1–Hus1 complex (9–1–1) in DNA damage response, and with apurinic/apyrimidinic endonuclease 1 (APE1) in BER. However, the structural basis for the BER pathway by MUTYH and its interacting proteins is unclear. Here, we determined the crystal structures of complexes between mouse MUTYH and DNA, and between the C-terminal domain of mouse MUTYH and human PCNA. The structures elucidated the repair mechanism for the A:8-oxoG mispair including DNA replication-coupled repair process involving MUTYH and PCNA. The Zn-binding motif was revealed to comprise one histidine and three cysteine residues. The IDC, including the Zn-binding motif, is exposed on the MUTYH surface, suggesting its interaction modes with 9–1–1 and APE1, respectively. The structure of MUTYH explains how MAP mutations perturb MUTYH function.
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Affiliation(s)
- Teruya Nakamura
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, 862-0973 Kumamoto, Japan.,Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, 862-0973 Kumamoto, Japan
| | - Kohtaro Okabe
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, 862-0973 Kumamoto, Japan
| | - Shogo Hirayama
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, 862-0973 Kumamoto, Japan
| | - Mami Chirifu
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, 862-0973 Kumamoto, Japan
| | - Shinji Ikemizu
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, 862-0973 Kumamoto, Japan
| | - Hiroshi Morioka
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, 862-0973 Kumamoto, Japan
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yuriko Yamagata
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, 862-0973 Kumamoto, Japan.,Shokei University and Shokei University Junior College, 2-6-78, Kuhonji, Chuo-ku, Kumamoto, 862-8678 Kumamoto, Japan
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23
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Apurinic/Apyrimidinic Endonuclease 2 (APE2): An ancillary enzyme for contextual base excision repair mechanisms to preserve genome stability. Biochimie 2021; 190:70-90. [PMID: 34302888 DOI: 10.1016/j.biochi.2021.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/29/2021] [Accepted: 07/19/2021] [Indexed: 01/03/2023]
Abstract
The genome of living organisms frequently undergoes various types of modifications which are recognized and repaired by the relevant repair mechanisms. These repair pathways are increasingly being deciphered to understand the mechanisms. Base excision repair (BER) is indispensable to maintain genome stability. One of the enigmatic repair proteins of BER, Apurinic/Apyrimidinic Endonuclease 2 (APE2), like APE1, is truly multifunctional and demonstrates the independent and non-redundant function in maintaining the genome integrity. APE2 is involved in ATR-Chk1 mediated DNA damage response. It also resolves topoisomerase1 mediated cleavage complex intermediate which is formed while repairing misincorporated ribonucleotides in the absence of functional RNase H2 mediated excision repair pathway. BER participates in the demethylation pathway and the role of Arabidopsis thaliana APE2 is demonstrated in this process. Moreover, APE2 is synthetically lethal to BRCA1, BRCA2, and RNase H2, and its homolog, APE1 fails to complement the function. Hence, the role of APE2 is not just an alternate to the repair mechanisms but has implications in diverse functional pathways related to the maintenance of genome integrity. This review analyses genomic features of APE2 and delineates its enzyme function as error-prone as well as efficient and accurate repair protein based on the studies on mammalian or its homolog proteins from model systems such as Arabidopsis thaliana, Schizosaccharomyces pombe, Trypanosoma curzi, Xenopus laevis, Danio rerio, Mus musculus, and Homo sapiens.
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24
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Leu M, Riebeling T, Dröge LH, Hubert L, Guhlich M, Wolff HA, Brockmöller J, Gaedcke J, Rieken S, Schirmer MA. 8-Oxoguanine DNA Glycosylase (OGG1) Cys326 Variant: Increased Risk for Worse Outcome of Patients with Locally Advanced Rectal Cancer after Multimodal Therapy. Cancers (Basel) 2021; 13:cancers13112805. [PMID: 34199885 PMCID: PMC8200071 DOI: 10.3390/cancers13112805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/17/2021] [Accepted: 05/31/2021] [Indexed: 11/16/2022] Open
Abstract
Despite excellent loco-regional control by multimodal treatment of locally advanced rectal cancer, a substantial portion of patients succumb to this disease. As many treatment effects are mediated via reactive oxygen species (ROS), we evaluated the effect of single nucleotide polymorphisms (SNPs) in ROS-related genes on clinical outcome. Based on the literature, eight SNPs in seven ROS-related genes were assayed. Eligible patients (n = 287) diagnosed with UICC stage II/III rectal cancer were treated multimodally starting with neoadjuvant radiochemotherapy (N-RCT) according to the clinical trial protocols of CAO/ARO/AIO-94, CAO/ARO/AIO-04, TransValid-A, and TransValid-B. The median follow-up was 64.4 months. The Ser326Cys polymorphism in the human OGG1 gene affected clinical outcome, in particular cancer-specific survival (CSS). This effect was comparable in extent to the ypN status, an already established strong prognosticator for patient outcome. Homozygous and heterozygous carriers of the Cys326 variant (n = 105) encountered a significantly worse CSS (p = 0.0004 according to the log-rank test, p = 0.01 upon multiple testing adjustment). Cox regression elicited a hazard ratio for CSS of 3.64 (95% confidence interval 1.70-7.78) for patients harboring the Cys326 allele. In a multivariable analysis, the effect of Cys326 on CSS was preserved. We propose the genetic polymorphism Ser326Cys as a promising biomarker for outcome in rectal cancer.
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Affiliation(s)
- Martin Leu
- Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany; (M.L.); (T.R.); (L.H.D.); (L.H.); (M.G.); (H.A.W.); (S.R.)
| | - Theresa Riebeling
- Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany; (M.L.); (T.R.); (L.H.D.); (L.H.); (M.G.); (H.A.W.); (S.R.)
- Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Leif Hendrik Dröge
- Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany; (M.L.); (T.R.); (L.H.D.); (L.H.); (M.G.); (H.A.W.); (S.R.)
| | - Laura Hubert
- Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany; (M.L.); (T.R.); (L.H.D.); (L.H.); (M.G.); (H.A.W.); (S.R.)
| | - Manuel Guhlich
- Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany; (M.L.); (T.R.); (L.H.D.); (L.H.); (M.G.); (H.A.W.); (S.R.)
| | - Hendrik Andreas Wolff
- Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany; (M.L.); (T.R.); (L.H.D.); (L.H.); (M.G.); (H.A.W.); (S.R.)
- Medical Center, Department of Radiation Oncology, University of Regensburg, 93053 Regensburg, Germany
| | - Jürgen Brockmöller
- Institute of Clinical Pharmacology, University Medical Center Göttingen, 37075 Göttingen, Germany;
| | - Jochen Gaedcke
- Clinic of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany;
| | - Stefan Rieken
- Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany; (M.L.); (T.R.); (L.H.D.); (L.H.); (M.G.); (H.A.W.); (S.R.)
| | - Markus Anton Schirmer
- Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany; (M.L.); (T.R.); (L.H.D.); (L.H.); (M.G.); (H.A.W.); (S.R.)
- Institute of Clinical Pharmacology, University Medical Center Göttingen, 37075 Göttingen, Germany;
- Correspondence: ; Tel.: +49-551-39-8866
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25
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Rong Z, Tu P, Xu P, Sun Y, Yu F, Tu N, Guo L, Yang Y. The Mitochondrial Response to DNA Damage. Front Cell Dev Biol 2021; 9:669379. [PMID: 34055802 PMCID: PMC8149749 DOI: 10.3389/fcell.2021.669379] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/20/2021] [Indexed: 01/08/2023] Open
Abstract
Mitochondria are double membrane organelles in eukaryotic cells that provide energy by generating adenosine triphosphate (ATP) through oxidative phosphorylation. They are crucial to many aspects of cellular metabolism. Mitochondria contain their own DNA that encodes for essential proteins involved in the execution of normal mitochondrial functions. Compared with nuclear DNA, the mitochondrial DNA (mtDNA) is more prone to be affected by DNA damaging agents, and accumulated DNA damages may cause mitochondrial dysfunction and drive the pathogenesis of a variety of human diseases, including neurodegenerative disorders and cancer. Therefore, understanding better how mtDNA damages are repaired will facilitate developing therapeutic strategies. In this review, we focus on our current understanding of the mtDNA repair system. We also discuss other mitochondrial events promoted by excessive DNA damages and inefficient DNA repair, such as mitochondrial fusion, fission, and mitophagy, which serve as quality control events for clearing damaged mtDNA.
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Affiliation(s)
- Ziye Rong
- Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, China
| | - Peipei Tu
- Department of Microbiology and Bioengineering, School of Life Sciences, Anhui Medical University, Hefei, China
| | - Peiqi Xu
- Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, China
| | - Yan Sun
- Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, China
| | - Fangfang Yu
- Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, China
| | - Na Tu
- Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, China
| | - Lixia Guo
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, United States
| | - Yanan Yang
- Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, China
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26
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Wang W, Ma Y, Huang M, Liang W, Zhao X, Li Q, Wang S, Hu Z, He L, Gao T, Chen J, Pan F, Guo Z. Asymmetrical arginine dimethylation of histone H4 by 8-oxog/OGG1/PRMT1 is essential for oxidative stress-induced transcription activation. Free Radic Biol Med 2021; 164:175-186. [PMID: 33418111 DOI: 10.1016/j.freeradbiomed.2020.12.457] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 01/09/2023]
Abstract
It has been established that 8-oxoguanine DNA glycosylase 1 (OGG1) is the main enzyme removing oxidized guanine under oxidative stress. However, increasing evidence has shown that OGG1 is not only a base excision repair protein but also a new transcriptional coactivator involved in oxidative stress-induced gene expression. Its downstream target genes and the underlying regulatory mechanisms still need to be discerned. Here, it was discovered that c-Myc is a downstream target of OGG1 under oxidative stress and that H4R3me2a is involved in this transcriptional regulation. The increased level of H4R3me2a induced by H2O2 is regulated by OGG1, which may directly interact with the specific arginine methyltransferase PRMT1 and promote the asymmetrical dimethylation of H4R3me1. H4R3me2a enrichment on the promoter of c-Myc can recruit YY1 and activate c-Myc transcription. Moreover, knocking down OGG1 or PRMT1 suppresses c-Myc transcription under oxidative stress by downregulating H4R3me2a formation. Furthermore, the overexpression of wild type (WT) H4R3 promotes c-Myc transcription, but the expression of mutant H4R3Q does not have this effect. Taken together, our data show that the 8-oxoG/OGG1/PRMT1/H4R3me2a/YY1 axis senses oxidative stress and promotes gene transcription.
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Affiliation(s)
- Wentao Wang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Ying Ma
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Miaoling Huang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Weichu Liang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Xingqi Zhao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Qianwen Li
- Department of Radiotherapy, Taikang Xianlin Drum Tower Hospital, Nanjing University, Nanjing, 210000, China
| | - Shiwei Wang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Zhigang Hu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Lingfeng He
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Tao Gao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Jinfei Chen
- Department of Radiotherapy, Taikang Xianlin Drum Tower Hospital, Nanjing University, Nanjing, 210000, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Feiyan Pan
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China.
| | - Zhigang Guo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China.
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27
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Komakula SSB, Blaze B, Ye H, Dobrzyn A, Sampath H. A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis. Int J Mol Sci 2021; 22:ijms22031152. [PMID: 33503804 PMCID: PMC7865743 DOI: 10.3390/ijms22031152] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/05/2021] [Accepted: 01/14/2021] [Indexed: 12/13/2022] Open
Abstract
Cells sustain constant oxidative stress from both exogenous and endogenous sources. When unmitigated by antioxidant defenses, reactive oxygen species damage cellular macromolecules, including DNA. Oxidative lesions in both nuclear and mitochondrial DNA are repaired via the base excision repair (BER) pathway, initiated by DNA glycosylases. We have previously demonstrated that the BER glycosylase 8-oxoguanine DNA glycosylase (OGG1) plays a novel role in body weight maintenance and regulation of adiposity. Specifically, mice lacking OGG1 (Ogg1−/−) are prone to increased fat accumulation with age and consumption of hypercaloric diets. Conversely, transgenic animals with mitochondrially-targeted overexpression of OGG1 (Ogg1Tg) are resistant to age- and diet-induced obesity. Given these phenotypes of altered adiposity in the context of OGG1 genotype, we sought to determine if OGG1 plays a cell-intrinsic role in adipocyte maturation and lipid accumulation. Here, we report that preadipocytes from Ogg1−/− mice differentiate more efficiently and accumulate more lipids than those from wild-type animals. Conversely, OGG1 overexpression significantly blunts adipogenic differentiation and lipid accretion in both pre-adipocytes from Ogg1Tg mice, as well as in 3T3-L1 cells with adenovirus-mediated OGG1 overexpression. Mechanistically, changes in adipogenesis are accompanied by significant alterations in cellular PARylation, corresponding with OGG1 genotype. Specifically, deletion of OGG1 reduces protein PARylation, concomitant with increased adipogenic differentiation, while OGG1 overexpression significantly increases PARylation and blunts adipogenesis. Collectively, these data indicate a novel role for OGG1 in modulating adipocyte differentiation and lipid accretion. These findings have important implications to our knowledge of the fundamental process of adipocyte differentiation, as well as to our understanding of lipid-related diseases such as obesity.
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Affiliation(s)
- Sai Santosh Babu Komakula
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA; (S.S.B.K.); (B.B.); (H.Y.)
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;
| | - Bhavya Blaze
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA; (S.S.B.K.); (B.B.); (H.Y.)
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
| | - Hong Ye
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA; (S.S.B.K.); (B.B.); (H.Y.)
| | - Agnieszka Dobrzyn
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;
| | - Harini Sampath
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA; (S.S.B.K.); (B.B.); (H.Y.)
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
- Center for Microbiome, Nutrition, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA
- Correspondence:
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28
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Fontana GA, Gahlon HL. Mechanisms of replication and repair in mitochondrial DNA deletion formation. Nucleic Acids Res 2020; 48:11244-11258. [PMID: 33021629 PMCID: PMC7672454 DOI: 10.1093/nar/gkaa804] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/07/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Deletions in mitochondrial DNA (mtDNA) are associated with diverse human pathologies including cancer, aging and mitochondrial disorders. Large-scale deletions span kilobases in length and the loss of these associated genes contributes to crippled oxidative phosphorylation and overall decline in mitochondrial fitness. There is not a united view for how mtDNA deletions are generated and the molecular mechanisms underlying this process are poorly understood. This review discusses the role of replication and repair in mtDNA deletion formation as well as nucleic acid motifs such as repeats, secondary structures, and DNA damage associated with deletion formation in the mitochondrial genome. We propose that while erroneous replication and repair can separately contribute to deletion formation, crosstalk between these pathways is also involved in generating deletions.
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Affiliation(s)
- Gabriele A Fontana
- Department of Health Sciences and Technology, ETH Zürich, Schmelzbergstrasse 9, 8092 Zürich, Switzerland
| | - Hailey L Gahlon
- To whom correspondence should be addressed. Tel: +41 44 632 3731;
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29
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Mitochondrial Dysfunction in Parkinson's Disease: Focus on Mitochondrial DNA. Biomedicines 2020; 8:biomedicines8120591. [PMID: 33321831 PMCID: PMC7763033 DOI: 10.3390/biomedicines8120591] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/05/2020] [Accepted: 12/08/2020] [Indexed: 12/14/2022] Open
Abstract
Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models. This suggests nuclear suppression of the mitochondrial defects, which obviously involve cross-talk between nuclear and mitochondrial genomes for maintenance of mitochondrial functioning.
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30
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Ma Z, Wang W, Wang S, Zhao X, Ma Y, Wu C, Hu Z, He L, Pan F, Guo Z. Symmetrical dimethylation of H4R3: A bridge linking DNA damage and repair upon oxidative stress. Redox Biol 2020; 37:101653. [PMID: 32739156 PMCID: PMC7767741 DOI: 10.1016/j.redox.2020.101653] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/27/2020] [Accepted: 07/20/2020] [Indexed: 01/31/2023] Open
Abstract
The DNA lesions caused by oxidative damage are principally repaired by the base excision repair (BER) pathway. 8-oxoguanine DNA glycosylase 1 (OGG1) initiates BER through recognizing and cleaving the oxidatively damaged nucleobase 8-oxo-7,8-dihydroguanine (8-oxoG). How the BER machinery detects and accesses lesions within the context of chromatin is largely unknown. Here, we found that the symmetrical dimethylarginine of histone H4 (producing H4R3me2s) serves as a bridge between DNA damage and subsequent repair. Intracellular H4R3me2s was significantly increased after treatment with the DNA oxidant reagent H2O2, and this increase was regulated by OGG1, which could directly interact with the specific arginine methyltransferase, PRMT5. Arginine-methylated H4R3 could associate with flap endonuclease 1 (FEN1) and enhance its nuclease activity and BER efficiency. Furthermore, cells with a decreased level of H4R3me2s were more susceptible to DNA-damaging agents and accumulated more DNA damage lesions in their genome. Taken together, these results demonstrate that H4R3me2s can be recognized as a reader protein that senses DNA damage and a writer protein that promotes DNA repair.
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Affiliation(s)
- Zhuang Ma
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China; Institute of DNA Repair Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wentao Wang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China; Department of Health Technology, Technical University of Denmark, Kongens Lyngby DK-2800, Denmark
| | - Shiwei Wang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Xingqi Zhao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Ying Ma
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Congye Wu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68, Changle Road, Nanjing, 210006, China
| | - Zhigang Hu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Lingfeng He
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China
| | - Feiyan Pan
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China.
| | - Zhigang Guo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023, China.
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Inokuchi S, Itoh S, Yoshizumi T, Yugawa K, Yoshiya S, Toshima T, Takeishi K, Iguchi T, Sanefuji K, Harada N, Sugimachi K, Ikegami T, Kohashi K, Taguchi K, Yonemasu H, Fukuzawa K, Oda Y, Mori M. Mitochondrial expression of the DNA repair enzyme OGG1 improves the prognosis of pancreatic ductal adenocarcinoma. Pancreatology 2020; 20:1175-1182. [PMID: 32741713 DOI: 10.1016/j.pan.2020.07.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 07/05/2020] [Accepted: 07/17/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES 8-Hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and causes transversion mutations and carcinogenesis. 8-OHdG is excision repaired by 8-OHdG DNA glycosylase 1 (OGG1), which is classified as nuclear and mitochondrial subtypes. We aimed to clarify the role of OGG1 in pancreatic ductal adenocarcinoma (PDAC). METHODS Ninety-two patients with PDAC who had undergone surgical resection at multiple institutions were immunohistochemically analyzed. The OGG1 and 8-OHdG expression levels were scored using the Germann Immunoreactive Score. The cutoff values of OGG1, as well as that of 8-OHdG, were determined. RESULTS The low nuclear OGG1 expression group (n = 41) showed significantly higher carbohydrate antigen (CA)19-9 (p = 0.026), and higher s-pancreas antigen (SPAN)-1 (p = 0.017) than the high expression group (n = 51). Nuclear OGG1 expression has no effect on the prognosis. The low mitochondrial OGG1 expression group (n = 40) showed higher CA19-9 (p = 0.041), higher SPAN-1 (p = 0.032), and more histological perineural invasion (p = 0.037) than the high expression group (n = 52). The low mitochondrial OGG1 expression group had a significantly shorter recurrence-free survival (p = 0.0080) and overall survival (p = 0.0073) rates. The Cox proportional hazards model revealed that low mitochondrial OGG1 expression is an independent risk factor of the PDAC prognosis. OGG1 expression was negatively correlated with 8-OHdG expression (p = 0.0004), and high 8-OHdG expression shortened the recurrence-free survival of patients with PDAC. CONCLUSIONS Low mitochondrial OGG1 expression might aggravate the PDAC prognosis.
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Affiliation(s)
- Shoichi Inokuchi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan.
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan
| | - Kyohei Yugawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan; Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, 812-8582, Japan
| | - Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan
| | - Kazuki Takeishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan
| | - Tomohiro Iguchi
- Department of Hepatobiliary-Pancreatic Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, 811-1395, Japan
| | - Kensaku Sanefuji
- Department of Surgery, Oita Red Cross Hospital, 870-0033, Oita, Japan
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan
| | - Keishi Sugimachi
- Department of Hepatobiliary-Pancreatic Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, 811-1395, Japan
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, 812-8582, Japan
| | - Kenichi Taguchi
- Department of Pathology, National Hospital Organization Kyushu Cancer Center, Fukuoka, 811-1395, Japan
| | - Hirotoshi Yonemasu
- Department of Anatomic Pathology, Oita Red Cross Hospital, 870-0033, Oita, Japan
| | - Kengo Fukuzawa
- Department of Surgery, Oita Red Cross Hospital, 870-0033, Oita, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, 812-8582, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 812-8582, Fukuoka, Japan
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Yugawa K, Itoh S, Yoshizumi T, Yoshiya S, Takeishi K, Toshima T, Harada N, Ikegami T, Kohashi K, Oda Y, Mori M. Prognostic impact of 8-hydroxy-deoxyguanosine and its repair enzyme 8-hydroxy-deoxyguanosine DNA glycosylase in hepatocellular carcinoma. Pathol Int 2020; 70:533-541. [PMID: 32419286 DOI: 10.1111/pin.12952] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/26/2020] [Accepted: 05/03/2020] [Indexed: 12/22/2022]
Abstract
Hepatocellular carcinoma (HCC) has a poor prognosis in the setting of chronic inflammation and fibrosis, both of which promote nuclear DNA oxidative damage. 8-hydroxy-deoxyguanosine (8-OHdG) DNA glycosylase (OGG1) enhances the repair of 8-OHdG, which is the primary oxidative stress-induced mutation that leads to malignant alterations. This study aims to clarify the relationships between oxidative stress-induced factors and HCC progression. The clinicopathological factors were compared with immunohistochemistry OGG1 and 8-OHdG expressions in 86 resected HCC specimens. High 8-OHdG expression was associated with high serum aspartate transaminase and total bilirubin levels, as well as a low platelet count, compared with low 8-OHdG expression. Histological liver cirrhosis and poor differentiation were more frequent in patients with high 8-OHdG expression than in those with low 8-OHdG expression. The 8-OHdG was negatively correlated with OGG1 expression in HCC patients. Therefore, we classified the patients into two groups, low OGG1/high 8-OHdG group and the other group. The patients with low OGG1/high 8-OHdG expressions had worse prognosis than those with the other expressions. Our results showed that low OGG1/high 8-OHdG expressions in nuclei influence HCC patient outcomes. Evaluating the patterns of OGG1 and 8-OHdG expressions might provide pivotal prognostic biomarkers in patients with HCC.
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Affiliation(s)
- Kyohei Yugawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuki Takeishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Kodavati M, Wang H, Hegde ML. Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective. Cells 2020; 9:cells9041065. [PMID: 32344665 PMCID: PMC7226538 DOI: 10.3390/cells9041065] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/15/2020] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Mitochondria plays privotal role in diverse pathways that regulate cellular function and survival, and have emerged as a prime focus in aging and age-associated motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Accumulating evidence suggests that many amyloidogenic proteins, including MND-associated RNA/DNA-binding proteins fused in sarcoma (FUS) and TAR DNA binding protein (TDP)-43, are strongly linked to mitochondrial dysfunction. Animal model and patient studies have highlighted changes in mitochondrial structure, plasticity, replication/copy number, mitochondrial DNA instability, and altered membrane potential in several subsets of MNDs, and these observations are consistent with the evidence of increased excitotoxicity, induction of reactive oxygen species, and activation of intrinsic apoptotic pathways. Studies in MND rodent models also indicate that mitochondrial abnormalities begin prior to the clinical and pathological onset of the disease, suggesting a causal role of mitochondrial dysfunction. Our recent studies, which demonstrated the involvement of specific defects in DNA break-ligation mediated by DNA ligase 3 (LIG3) in FUS-associated ALS, raised a key question of its potential implication in mitochondrial DNA transactions because LIG3 is essential for both mitochondrial DNA replication and repair. This question, as well as how wild-type and mutant MND-associated factors affect mitochondria, remain to be elucidated. These new investigation avenues into the mechanistic role of mitochondrial dysfunction in MNDs are critical to identify therapeutic targets to alleviate mitochondrial toxicity and its consequences. In this article, we critically review recent advances in our understanding of mitochondrial dysfunction in diverse subgroups of MNDs and discuss challenges and future directions.
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Affiliation(s)
- Manohar Kodavati
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (M.K.); (H.W.)
| | - Haibo Wang
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (M.K.); (H.W.)
| | - Muralidhar L. Hegde
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (M.K.); (H.W.)
- Department of Neurosurgery, Weill Medical College, New York, NY 10065, USA
- Correspondence:
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Kose O, Rachidi W, Beal D, Erkekoglu P, Fayyad-Kazan H, Kocer Gumusel B. The effects of different bisphenol derivatives on oxidative stress, DNA damage and DNA repair in RWPE-1 cells: A comparative study. J Appl Toxicol 2019; 40:643-654. [PMID: 31875995 DOI: 10.1002/jat.3934] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Bisphenol A (BPA) is a well-known endocrine disruptor and it is widely used mainly in the plastics industry. Due to recent reports on its possible impact on health (particularly on the male reproductive system), bisphenol F (BPF) and bisphenol S (BPS) are now being used as alternatives. In this study, RWPE-1 cells were used as a model to compare cytotoxicity, oxidative stress-causing potential and genotoxicity of these chemicals. In addition, the effects of the bisphenol derivatives were assessed on DNA repair proteins. RWPE-1 cells were incubated with BPA, BPF, and BPS at concentrations of 0-600 μM for 24 h. The inhibitory concentration 20 (IC20 , concentration that causes 20% of cell viability loss) values for BPA, BPF, and BPS were 45, 65, and 108 μM, respectively. These results indicated that cytotoxicity potentials were ranked as BPA > BPF > BPS. We also found alterations in superoxide dismutase, glutathione peroxidase and glutathione reductase activities, and glutathione and total antioxidant capacity in all bisphenol-exposed groups. In the standard and modified Comet assay, BPS produced significantly higher levels of DNA damage vs the control. DNA repair proteins (OGG1, Ape-1, and MyH) involved in the base excision repair pathway, as well as p53 protein levels were down-regulated in all of the bisphenol-exposed groups. We found that the BPA alternatives were also cytotoxic and genotoxic, and changed the expressions of DNA repair enzymes. Therefore, further studies are needed to assess whether they can be used safely as alternatives to BPA or not.
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Affiliation(s)
- Ozge Kose
- Faculty of Pharmacy, Department of Toxicology, Sıhhiye, Hacettepe University, Ankara, Turkey
| | - Walid Rachidi
- Faculté de Médecine-Pharmacie¸ Domaine de la Merci, University Grenoble Alpes, Grenoble, France.,Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA), Institut Nanosciences et Cryogénie (INAC), Systèmes Moléculaires et NanoMatériaux pour l'Energie et la Santé (SyMMES), Lésions des Acides Nucléiques (LAN), Grenoble, France
| | - David Beal
- Faculté de Médecine-Pharmacie¸ Domaine de la Merci, University Grenoble Alpes, Grenoble, France.,Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA), Institut Nanosciences et Cryogénie (INAC), Systèmes Moléculaires et NanoMatériaux pour l'Energie et la Santé (SyMMES), Lésions des Acides Nucléiques (LAN), Grenoble, France
| | - Pınar Erkekoglu
- Faculty of Pharmacy, Department of Toxicology, Sıhhiye, Hacettepe University, Ankara, Turkey
| | - Hussein Fayyad-Kazan
- Faculty of Sciences I, Laboratory of Cancer Biology and Molecular Immunology, Lebanese University, Hadath, Lebanon
| | - Belma Kocer Gumusel
- Faculty of Pharmacy, Department of Toxicology, Lokman Hekim University, Ankara, Turkey
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Zhao C, Yang J, Xu L. The hOGG1 Ser326Cys polymorphism and esophageal cancer risk: a meta-analysis of 1,875 cancer cases and 3,041 controls. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:438. [PMID: 31700874 DOI: 10.21037/atm.2019.08.121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Recently, there have been several studies that have looked at the association between hOGG1 Ser326Cys polymorphism and esophageal cancer (EC) risk. However, the results of previous reports remain controversial and ambiguous. Thus, we performed a meta-analysis to explore more precisely the association between hOGG1 Ser326Cys polymorphism and the risk of EC. Methods A meta-analysis was performed to examine the association between hOGG1 Ser326Cys polymorphism and EC risk. Odds ratio (OR) and its 95% confidence interval (CI) were used for statistical analysis. Results Our publication search identified a total of 9 studies with 1,875 cases and 3,041 controls. There was no significant associations in all genetic models between hOGG1 Ser326Cys polymorphism and EC observed (OR =1.024, 95% CI: 0.932-1.125 for Cys vs. Ser, P=0.624; OR =1.126, 95% CI: 0.901-1.408 for Cys/Cys vs. Ser/Ser, P=0.296; OR = 0.961, 95% CI: 0.844-1.093 for Ser/Cys vs. Ser/Ser, P =0.540; OR =0.989, 95% CI: 0.874-1.118 for Cys/Cys + Ser/Cys vs. Ser/Ser, P=0.855; OR =1.165, 95% CI: 0.945-1.436 for Cys/Cys vs. Ser/Cys + Ser/Ser, P=0.153). Also, in the stratified analyses by ethnicity and cancer type, no significant association was observed. Conclusions This meta-analysis on hOGG1 Ser326Cys polymorphism and the risk of EC suggests there is no statistically significant association between the two. Additional primary studies may be necessary to provide evidence of any significant association between this specific polymorphism and EC.
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Affiliation(s)
- Chen Zhao
- Institute of Physical Education, Huzhou University, Huzhou 313000, China
| | - Ji Yang
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Liqian Xu
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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Roldán-Arjona T, Ariza RR, Córdoba-Cañero D. DNA Base Excision Repair in Plants: An Unfolding Story With Familiar and Novel Characters. FRONTIERS IN PLANT SCIENCE 2019; 10:1055. [PMID: 31543887 PMCID: PMC6728418 DOI: 10.3389/fpls.2019.01055] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 07/30/2019] [Indexed: 05/05/2023]
Abstract
Base excision repair (BER) is a critical genome defense pathway that deals with a broad range of non-voluminous DNA lesions induced by endogenous or exogenous genotoxic agents. BER is a complex process initiated by the excision of the damaged base, proceeds through a sequence of reactions that generate various DNA intermediates, and culminates with restoration of the original DNA structure. BER has been extensively studied in microbial and animal systems, but knowledge in plants has lagged behind until recently. Results obtained so far indicate that plants share many BER factors with other organisms, but also possess some unique features and combinations. Plant BER plays an important role in preserving genome integrity through removal of damaged bases. However, it performs additional important functions, such as the replacement of the naturally modified base 5-methylcytosine with cytosine in a plant-specific pathway for active DNA demethylation.
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Affiliation(s)
- Teresa Roldán-Arjona
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Department of Genetics, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - Rafael R. Ariza
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Department of Genetics, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | - Dolores Córdoba-Cañero
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Department of Genetics, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
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Boldinova EO, Khairullin RF, Makarova AV, Zharkov DO. Isoforms of Base Excision Repair Enzymes Produced by Alternative Splicing. Int J Mol Sci 2019; 20:ijms20133279. [PMID: 31277343 PMCID: PMC6651865 DOI: 10.3390/ijms20133279] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 06/29/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023] Open
Abstract
Transcripts of many enzymes involved in base excision repair (BER) undergo extensive alternative splicing, but functions of the corresponding alternative splice variants remain largely unexplored. In this review, we cover the studies describing the common alternatively spliced isoforms and disease-associated variants of DNA glycosylases, AP-endonuclease 1, and DNA polymerase beta. We also discuss the roles of alternative splicing in the regulation of their expression, catalytic activities, and intracellular transport.
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Affiliation(s)
| | - Rafil F Khairullin
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 9 Parizhskoy Kommuny Str., 420012 Kazan, Russia
| | - Alena V Makarova
- RAS Institute of Molecular Genetics, 2 Kurchatova Sq., 123182 Moscow, Russia.
| | - Dmitry O Zharkov
- Novosibirsk State University, 1 Pirogova St., 630090 Novosibirsk, Russia.
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Ave., 630090 Novosibirsk, Russia.
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Molecular Pathophysiology of Insulin Depletion, Mitochondrial Dysfunction, and Oxidative Stress in Alzheimer’s Disease Brain. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1128:27-44. [DOI: 10.1007/978-981-13-3540-2_3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Haruyama N, Sakumi K, Katogi A, Tsuchimoto D, De Luca G, Bignami M, Nakabeppu Y. 8-Oxoguanine accumulation in aged female brain impairs neurogenesis in the dentate gyrus and major island of Calleja, causing sexually dimorphic phenotypes. Prog Neurobiol 2019; 180:101613. [PMID: 31026482 DOI: 10.1016/j.pneurobio.2019.04.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 03/16/2019] [Accepted: 04/19/2019] [Indexed: 12/13/2022]
Abstract
In mammals, including humans, MTH1 with 8-oxo-dGTPase and OGG1 with 8-oxoguanine DNA glycosylase minimize 8-oxoguanine accumulation in genomic DNA. We investigated age-related alterations in behavior, 8-oxoguanine levels, and neurogenesis in the brains of Mth1/Ogg1-double knockout (TO-DKO), Ogg1-knockout, and human MTH1-transgenic (hMTH1-Tg) mice. Spontaneous locomotor activity was significantly decreased in wild-type mice with age, and females consistently exhibited higher locomotor activity than males. This decrease was significantly suppressed in female but not male TO-DKO mice and markedly enhanced in female hMTH1-Tg mice. Long-term memory retrieval was impaired in middle-aged female TO-DKO mice. 8-Oxoguanine accumulation significantly increased in nuclear DNA, particularly in the dentate gyrus (DG), subventricular zone (SVZ) and major island of Calleja (ICjM) in middle-aged female TO-DKO mice. In middle-aged female TO-DKO mice, neurogenesis was severely impaired in SVZ and DG, accompanied by ICjM and DG atrophy. Conversely, expression of hMTH1 efficiently suppressed 8-oxoguanine accumulation in both SVZ and DG with hypertrophy of ICjM. These findings indicate that newborn neurons from SVZ maintain ICjM in the adult brain, and increased accumulation of 8-oxoguanine in nuclear DNA of neural progenitors in females is caused by 8-oxo-dGTP incorporation during proliferation, causing depletion of neural progenitors, altered behavior, and cognitive function changes with age.
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Affiliation(s)
- Naoki Haruyama
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kunihiko Sakumi
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Atsuhisa Katogi
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Daisuke Tsuchimoto
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Gabriele De Luca
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy
| | - Margherita Bignami
- Department of Environment and Health, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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Okumura K, Nishihara S, Inoue YH. Genetic identification and characterization of three genes that prevent accumulation of oxidative DNA damage in Drosophila adult tissues. DNA Repair (Amst) 2019; 78:7-19. [PMID: 30947023 DOI: 10.1016/j.dnarep.2019.02.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/22/2019] [Accepted: 02/25/2019] [Indexed: 01/29/2023]
Abstract
Reactive oxygen species generated in the process of energy production represent a major cause of oxidative DNA damage. Production of the oxidized guanine base, 8-oxo-guanine (8-oxoG), results in mismatched pairing with adenine and subsequently leads to G:C to T:A transversions after DNA replication. Our previous study demonstrated that Drosophila CG1795 encodes an ortholog of Ogg1, which is essential for the elimination of 8-oxoG. Moreover, the Drosophila ribosomal protein S3 (RpS3) possesses N-glycosylase activity that eliminates 8-oxoG in vitro. In this study, we show that RpS3 heterozygotes hyper-accumulate 8-oxoG in midgut cell nuclei after oxidant feeding, suggesting thatRpS3 is required for the elimination of 8-oxoG in Drosophila adults. We further showed that several muscle-aging phenotypes were significantly accelerated in RpS3 heterozygotes. Ogg1 is localized in the nucleus, while RpS3 is in the cytoplasm, closely associated with endoplasmic reticulum networks. Results of genetic analyses also suggest that these two proteins operate similarly but independently in the elimination of oxidized guanine bases from genomic DNA. Next, we obtained genetic evidence suggesting that CG42813 functions as the Drosophila ortholog of mammalian Mth1 in the elimination of oxidized dGTP (8-oxo-dGTP) from the nucleotide pool. Depletion of this gene significantly increased the number of DNA damage foci in the nuclei of Drosophila midgut cells. Furthermore, several aging-related phenotypes such as age-dependent loss of adult locomotor activities and accumulation of polyubiquitylated proteins in adult muscles were also significantly accelerated in CG42813-depleted flies. Lastly, we investigated the phenotype of adults depleted of CG9272, which encodes a protein with homology to mammalian Nth1 that is essential for the elimination of oxidized thymine. Excessive accumulation of oxidized bases was observed in the epithelial cell nuclei after oxidant feeding. In conclusion, three genes that prevent accumulation of oxidative DNA damage were identified in Drosophila.
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Affiliation(s)
- Kazuko Okumura
- Department of Insect Biomedical Research, Center for Advanced Insect Research Promotion, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-0962, Japan
| | - Shunta Nishihara
- Department of Insect Biomedical Research, Center for Advanced Insect Research Promotion, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-0962, Japan
| | - Yoshihiro H Inoue
- Department of Insect Biomedical Research, Center for Advanced Insect Research Promotion, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-0962, Japan.
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41
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Mitochondrial DNA Integrity: Role in Health and Disease. Cells 2019; 8:cells8020100. [PMID: 30700008 PMCID: PMC6406942 DOI: 10.3390/cells8020100] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/25/2019] [Accepted: 01/28/2019] [Indexed: 01/06/2023] Open
Abstract
As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.
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Cheng Z, Cheng N, Shi D, Ren X, Gan T, Bai Y, Yang K. The Relationship between Nkx2.1 and DNA Oxidative Damage Repair in Nickel Smelting Workers: Jinchang Cohort Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16010120. [PMID: 30621196 PMCID: PMC6339211 DOI: 10.3390/ijerph16010120] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 12/28/2018] [Accepted: 12/30/2018] [Indexed: 01/24/2023]
Abstract
Background: Occupational nickel exposure can cause DNA oxidative damage and influence DNA repair. However, the underlying mechanism of nickel-induced high-risk of lung cancer has not been fully understood. Our study aims to evaluate whether the nickel-induced oxidative damage and DNA repair were correlated with the alterations in Smad2 phosphorylation status and Nkx2.1 expression levels, which has been considered as the lung cancer initiation gene. Methods: 140 nickel smelters and 140 age-matched administrative officers were randomly stratified by service length from Jinchang Cohort. Canonical regression, χ2 test, Spearman correlation etc. were used to evaluate the association among service length, MDA, 8-OHdG, hOGG1, PARP, pSmad2, and Nkx2.1. Results: The concentrations of MDA, PARP, pSmad2, and Nkx2.1 significantly increased. Nkx2.1 (rs = 0.312, p < 0.001) and Smad2 phosphorylation levels (rs = 0.232, p = 0.006) were positively correlated with the employment length in nickel smelters, which was not observed in the administrative officer group. Also, elevation of Nkx2.1 expression was positively correlated with service length, 8-OHdG, PARP, hOGG1 and pSmad2 levels in nickel smelters. Conclusions: Occupational nickel exposure could increase the expression of Nkx2.1 and pSmad2, which correlated with the nickel-induced oxidative damage and DNA repair change.
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Affiliation(s)
- Zhiyuan Cheng
- Evidence-Based Medicine Centre, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.
- School of Public Health, Department of Epidemiology and Statistics, Lanzhou University, Lanzhou 730000, China.
| | - Ning Cheng
- Centre of Medical Laboratory, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, China.
| | - Dian Shi
- School of Public Health, Department of Epidemiology and Statistics, Lanzhou University, Lanzhou 730000, China.
| | - Xiaoyu Ren
- School of Public Health, Department of Epidemiology and Statistics, Lanzhou University, Lanzhou 730000, China.
| | - Ting Gan
- School of Public Health, Department of Epidemiology and Statistics, Lanzhou University, Lanzhou 730000, China.
| | - Yana Bai
- School of Public Health, Department of Epidemiology and Statistics, Lanzhou University, Lanzhou 730000, China.
| | - Kehu Yang
- Evidence-Based Medicine Centre, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.
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Abstract
The mitochondrial genome encodes proteins essential for the oxidative phosphorylation and, consequently, for proper mitochondrial function. Its localization and, possibly, structural organization contribute to higher DNA damage accumulation, when compared to the nuclear genome. In addition, the mitochondrial genome mutates at rates several times higher than the nuclear, although the causal relationship between these events are not clearly established. Maintaining mitochondrial DNA stability is critical for cellular function and organismal fitness, and several pathways contribute to that, including damage tolerance and bypass, degradation of damaged genomes and DNA repair. Despite initial evidence suggesting that mitochondria lack DNA repair activities, most DNA repair pathways have been at least partially characterized in mitochondria from several model organisms, including humans. In this chapter, we review what is currently known about how the main DNA repair pathways operate in mitochondria and contribute to mitochondrial DNA stability, with focus on the enzymology of mitochondrial DNA repair.
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Affiliation(s)
- Rebeca R Alencar
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Caio M P F Batalha
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Thiago S Freire
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Nadja C de Souza-Pinto
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
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44
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Komakula SSB, Tumova J, Kumaraswamy D, Burchat N, Vartanian V, Ye H, Dobrzyn A, Lloyd RS, Sampath H. The DNA Repair Protein OGG1 Protects Against Obesity by Altering Mitochondrial Energetics in White Adipose Tissue. Sci Rep 2018; 8:14886. [PMID: 30291284 PMCID: PMC6173743 DOI: 10.1038/s41598-018-33151-1] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 09/21/2018] [Indexed: 12/15/2022] Open
Abstract
Obesity and related metabolic pathologies represent a significant public health concern. Obesity is associated with increased oxidative stress that damages genomic and mitochondrial DNA. Oxidatively-induced lesions in both DNA pools are repaired via the base-excision repair pathway, initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). Global deletion of OGG1 and common OGG1 polymorphisms render mice and humans susceptible to metabolic disease. However, the relative contribution of mitochondrial OGG1 to this metabolic phenotype is unknown. Here, we demonstrate that transgenic targeting of OGG1 to mitochondria confers significant protection from diet-induced obesity, insulin resistance, and adipose tissue inflammation. These favorable metabolic phenotypes are mediated by an increase in whole body energy expenditure driven by specific metabolic adaptations, including increased mitochondrial respiration in white adipose tissue of OGG1 transgenic (Ogg1Tg) animals. These data demonstrate a critical role for a DNA repair protein in modulating mitochondrial energetics and whole-body energy balance.
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Affiliation(s)
- Sai Santosh Babu Komakula
- Department of Nutritional Sciences and Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA.,Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Jana Tumova
- Department of Nutritional Sciences and Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA
| | - Deeptha Kumaraswamy
- Department of Nutritional Sciences and Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA
| | - Natalie Burchat
- Department of Nutritional Sciences and Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA
| | - Vladimir Vartanian
- Oregon Institute of Occupational Health Sciences, Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Hong Ye
- Department of Nutritional Sciences and Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA
| | - Agnieszka Dobrzyn
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - R Stephen Lloyd
- Oregon Institute of Occupational Health Sciences, Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Harini Sampath
- Department of Nutritional Sciences and Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA.
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45
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Vlahopoulos S, Adamaki M, Khoury N, Zoumpourlis V, Boldogh I. Roles of DNA repair enzyme OGG1 in innate immunity and its significance for lung cancer. Pharmacol Ther 2018; 194:59-72. [PMID: 30240635 DOI: 10.1016/j.pharmthera.2018.09.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cytokines are pivotal mediators of the immune response, and their coordinated expression protects host tissue from excessive damage and oxidant stress. Nevertheless, the development of lung pathology, including asthma, chronic obstructive pulmonary disease, and ozone-induced lung injury, is associated with oxidant stress; as evidence, there is a significant increase in levels of the modified guanine base 7,8-dihydro-8-oxoguanine (8-oxoG) in the genome. 8-OxoG is primarily recognized by 8-oxoguanine glycosylase 1 (OGG1), which catalyzes the first step in the DNA base excision repair pathway. However, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, including NF-κB, to their cognate sites to enable expression of cytokines and chemokines, with ensuing recruitments of inflammatory cells. Hence, defective OGG1 will modulate the coordination between innate and adaptive immunity through excessive oxidant stress and cytokine dysregulation. Both oxidant stress and cytokine dysregulation constitute key elements of oncogenesis by KRAS, which is mechanistically coupled to OGG1. Thus, analysis of the mechanism by which OGG1 modulates gene expression helps discern between beneficial and detrimental effects of oxidant stress, exposes a missing functional link as a marker, and yields a novel target for lung cancer.
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Affiliation(s)
- Spiros Vlahopoulos
- Ηoremeio Research Laboratory, First Department of Paediatrics, National and Kapodistrian University of Athens, 11527 Athens, Greece.
| | - Maria Adamaki
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece
| | - Nikolas Khoury
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece
| | - Istvan Boldogh
- Departments of Microbiology and Immunology and the Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
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46
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Kasnak G, Könönen E, Syrjänen S, Gürsoy M, Zeidán-Chuliá F, Firatli E, Gürsoy UK. NFE2L2/NRF2, OGG1, and cytokine responses of human gingival keratinocytes against oxidative insults of various origin. Mol Cell Biochem 2018; 452:63-70. [PMID: 30030777 DOI: 10.1007/s11010-018-3412-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Accepted: 07/13/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Bacterial or tobacco-related insults induce oxidative stress in gingival keratinocytes. The aim of this study was to investigate anti-oxidative and cytokine responses of human gingival keratinocytes (HMK cells) against Porphyromonas gingivalis lipopolysaccharide (Pg LPS), nicotine, and 4-nitroquinoline N-oxide (4-NQO). MATERIALS AND METHODS HMK cells were incubated with Pg LPS (1 µl/ml), nicotine (1.54 mM), and 4-NQO (1 µM) for 24 h. Intracellular and extracellular levels of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1Ra), IL-8, monocyte chemoattractant protein (MCP)-1, and vascular endothelial growth factor (VEGF) were measured with the Luminex® xMAP™ technique, and nuclear factor, erythroid 2 like 2 (NFE2L2/NRF2) and 8-oxoguanine DNA glycosylase (OGG1) with Western blots. Data were statistically analyzed by two-way ANOVA with Bonferroni correction. RESULTS All tested oxidative stress inducers increased intracellular OGG1 levels, whereas only nicotine and 4-NQO induced NFE2L2/NRF2 levels. Nicotine, 4-NQO, and their combinational applications with Pg LPS induced the secretions of IL-1β and IL-1Ra, while that of IL-8 was inhibited by the presence of Pg LPS. MCP-1 secretion was suppressed by nicotine, alone and together with Pg LPS, while 4-NQO activated its secretion. Treatment of HMK cells with Pg LPS, nicotine, 4-NQO, or their combinations did not affect VEGF levels. CONCLUSION Pg LPS, nicotine, and 4-NQO induce oxidative stress and regulate anti-oxidative response and cytokine expressions in human gingival keratinocytes differently. These results may indicate that bacterial and tobacco-related insults regulate distinct pathways.
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Affiliation(s)
- Gökhan Kasnak
- Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, 20520, Turku, Finland. .,Faculty of Dentistry, Istanbul University, Istanbul, Turkey.
| | - Eija Könönen
- Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, 20520, Turku, Finland.,Welfare Division, Oral Health, City of Turku, Finland
| | - Stina Syrjänen
- Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, 20520, Turku, Finland.,Department of Pathology, Turku University Hospital, Turku, Finland
| | - Mervi Gürsoy
- Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, 20520, Turku, Finland
| | - Fares Zeidán-Chuliá
- Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, 20520, Turku, Finland.,Departamento de Ciencias Biomédicas Básicas, Facultad de Ciencias Biomédicas y de la Salud, Universidad Europea de Madrid, Madrid, Spain
| | - Erhan Firatli
- Faculty of Dentistry, Istanbul University, Istanbul, Turkey
| | - Ulvi K Gürsoy
- Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, 20520, Turku, Finland
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47
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Lia D, Reyes A, de Melo Campos JTA, Piolot T, Baijer J, Radicella JP, Campalans A. Mitochondrial maintenance under oxidative stress depends on mitochondrially localised α-OGG1. J Cell Sci 2018; 131:jcs213538. [PMID: 29848661 DOI: 10.1242/jcs.213538] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 05/21/2018] [Indexed: 12/18/2022] Open
Abstract
Accumulation of 8-oxoguanine (8-oxoG) in mitochondrial DNA and mitochondrial dysfunction have been observed in cells deficient for the DNA glycosylase OGG1 when exposed to oxidative stress. In human cells, up to eight mRNAs for OGG1 can be generated by alternative splicing and it is still unclear which of them codes for the protein that ensures the repair of 8-oxoG in mitochondria. Here, we show that the α-OGG1 isoform, considered up to now to be exclusively nuclear, has a functional mitochondrial-targeting sequence and is imported into mitochondria. We analyse the sub-mitochondrial localisation of α-OGG1 with unprecedented resolution and show that this DNA glycosylase is associated with DNA in mitochondrial nucleoids. We show that the presence of α-OGG1 inside mitochondria and its enzymatic activity are required to preserve the mitochondrial network in cells exposed to oxidative stress. Altogether, these results unveil a new role of α-OGG1 in the mitochondria and indicate that the same isoform ensures the repair of 8-oxoG in both nuclear and mitochondrial genomes. The activity of α-OGG1 in mitochondria is sufficient for the recovery of organelle function after oxidative stress.
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Affiliation(s)
- Debora Lia
- Institut de Biologie François Jacob (IBFJ), Institute of Cellular and Molecular Radiobiology, CEA, UMR967 INSERM, 96265 Fontenay aux Roses, France
- Université Paris Diderot/Université Paris-Sud, 96265 Fontenay aux Roses, France
| | - Aurelio Reyes
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, United Kingdom
| | - Julliane Tamara Araújo de Melo Campos
- Institut de Biologie François Jacob (IBFJ), Institute of Cellular and Molecular Radiobiology, CEA, UMR967 INSERM, 96265 Fontenay aux Roses, France
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN 59072-970, Brazil
| | - Tristan Piolot
- Institut Curie, CNRS UMR3215, INSERM U934, 75248 Paris, France
| | - Jan Baijer
- Institut de Biologie François Jacob (IBFJ), Institute of Cellular and Molecular Radiobiology, CEA, UMR967 INSERM, 96265 Fontenay aux Roses, France
- Université Paris Diderot/Université Paris-Sud, 96265 Fontenay aux Roses, France
| | - J Pablo Radicella
- Institut de Biologie François Jacob (IBFJ), Institute of Cellular and Molecular Radiobiology, CEA, UMR967 INSERM, 96265 Fontenay aux Roses, France
- Université Paris Diderot/Université Paris-Sud, 96265 Fontenay aux Roses, France
| | - Anna Campalans
- Institut de Biologie François Jacob (IBFJ), Institute of Cellular and Molecular Radiobiology, CEA, UMR967 INSERM, 96265 Fontenay aux Roses, France
- Université Paris Diderot/Université Paris-Sud, 96265 Fontenay aux Roses, France
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48
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miR-200a Modulates the Expression of the DNA Repair Protein OGG1 Playing a Role in Aging of Primary Human Keratinocytes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:9147326. [PMID: 29765508 PMCID: PMC5889889 DOI: 10.1155/2018/9147326] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 12/13/2017] [Accepted: 01/22/2018] [Indexed: 12/20/2022]
Abstract
Oxidative DNA damage accumulation may induce cellular senescence. Notably, senescent cells accumulate in aged tissues and are present at the sites of age-related pathologies. Although the signaling of DNA strand breaks has been extensively studied, the role of oxidative base lesions has not fully investigated in primary human keratinocyte aging. In this study, we show that primary human keratinocytes from elderly donors are characterized by a significant accumulation of the oxidative base lesion 8-OH-dG, impairment of oxidative DNA repair, and increase of miR-200a levels. Notably, OGG1-2a, a critical enzyme for 8-OH-dG repair, is a direct target of miR-200a and its expression levels significantly decrease in aged keratinocytes. The 8-OH-dG accumulation displays a significant linear relationship with the aging biomarker p16 expression during keratinocyte senescence. Interestingly, we found that miR-200a overexpression down-modulates its putative target Bmi-1, a well-known p16 repressor, and up-regulates p16 itself. miR-200a overexpression also up-regulates the NLRP3 inflammasome and IL-1β expression. Of note, primary keratinocytes from elderly donors are characterized by NRPL3 activation and IL-1β secretion. These findings point to miR-200a as key player in primary human keratinocyte aging since it is able to reduce oxidative DNA repair activity and may induce several senescence features through p16 and IL-1β up-regulation.
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49
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Qiao L, Feng X, Wang G, Zhou B, Yang Y, Li M. Polymorphisms in BER genes and risk of breast cancer: evidences from 69 studies with 33760 cases and 33252 controls. Oncotarget 2018; 9:16220-16233. [PMID: 29662639 PMCID: PMC5882330 DOI: 10.18632/oncotarget.23804] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
Recently, numerous studies have reported an association between single nucleotide polymorphisms in base-excision repair genes and the risk of developing breast cancer, however there is no consensus. The aim of this meta-analysis was to review and quantitatively assess the relationship between single nucleotide polymorphisms in base-excision repair genes and breast cancer risk. The results suggested that a mutation of T to G in rs1760944 may lead to a higher risk of developing breast cancer in the Mongoloid population, and G to A of rs25487 significantly reduced the risk of breast cancer in Mongoloid and Caucasoid populations. In contrast to the CC and CG genotypes, the GG genotype of rs1052133 located on theOGG1 gene appeared to be a protective factor against developing breast cancer in both Mongoloid and Caucasoid populations. There was no evidence to suggest that rs25489, rs1799782, rs1130409, rs1805414 and rs1136410 were associated with breast cancer risk. In conclusion, this study provides evidence to support the theory that DNA repair genes are associated with breast cancer risk, providing information to further understand breast cancer etiology. and The potential biological pathways linking DNA repair, ethnic background, environment and breast cancer require further investigation.
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Affiliation(s)
- Lele Qiao
- The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Xiaoshan Feng
- The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Gongping Wang
- The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Bo Zhou
- The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Yantong Yang
- The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Mengxiang Li
- Henan University of Science and Technology, LuoYang, Henan, 471023, China
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50
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Lee HT, Bose A, Lee CY, Opresko PL, Myong S. Molecular mechanisms by which oxidative DNA damage promotes telomerase activity. Nucleic Acids Res 2017; 45:11752-11765. [PMID: 28981887 PMCID: PMC5714237 DOI: 10.1093/nar/gkx789] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 09/14/2017] [Indexed: 11/13/2022] Open
Abstract
Telomeres are highly susceptible to oxidative DNA damage, which if left unrepaired can lead to dysregulation of telomere length homeostasis. Here we employed single molecule FRET, single molecule pull-down and biochemical analysis to investigate how the most common oxidative DNA lesions, 8-oxoguanine (8oxoG) and thymine glycol (Tg), regulate the structural properties of telomeric DNA and telomerase extension activity. In contrast to 8oxoG which disrupts the telomeric DNA structure, Tg exhibits substantially reduced perturbation of G-quadruplex folding. As a result, 8oxoG induces high accessibility, whereas Tg retains limited accessibility, of telomeric G-quadruplex DNA to complementary single stranded DNA and to telomere binding protein POT1. Surprisingly, the Tg lesion stimulates telomerase loading and activity to a similar degree as an 8oxoG lesion. We demonstrate that this unexpected stimulation arises from Tg-induced conformational alterations and dynamics in telomeric DNA. Despite impacting structure by different mechanisms, both 8oxoG and Tg enhance telomerase binding and extension activity to the same degree, potentially contributing to oncogenesis.
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Affiliation(s)
- Hui-Ting Lee
- Thomas C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD, 21218, USA
| | - Arindam Bose
- Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health and UPMC Hillman Cancer Center, Pittsburgh, PA 15261, USA
| | - Chun-Ying Lee
- Thomas C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD, 21218, USA
| | - Patricia L Opresko
- Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health and UPMC Hillman Cancer Center, Pittsburgh, PA 15261, USA
| | - Sua Myong
- Thomas C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD, 21218, USA.,Physics Frontier Center (Center for Physics of Living Cells), University of Illinois, 1110 W. Green St., Urbana, IL 61801, USA
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