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1
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Chiolo I, Altmeyer M, Legube G, Mekhail K. Nuclear and genome dynamics underlying DNA double-strand break repair. Nat Rev Mol Cell Biol 2025:10.1038/s41580-025-00828-1. [PMID: 40097581 DOI: 10.1038/s41580-025-00828-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2025] [Indexed: 03/19/2025]
Abstract
Changes in nuclear shape and in the spatial organization of chromosomes in the nucleus commonly occur in cancer, ageing and other clinical contexts that are characterized by increased DNA damage. However, the relationship between nuclear architecture, genome organization, chromosome stability and health remains poorly defined. Studies exploring the connections between the positioning and mobility of damaged DNA relative to various nuclear structures and genomic loci have revealed nuclear and cytoplasmic processes that affect chromosome stability. In this Review, we discuss the dynamic mechanisms that regulate nuclear and genome organization to promote DNA double-strand break (DSB) repair, genome stability and cell survival. Genome dynamics that support DSB repair rely on chromatin states, repair-protein condensates, nuclear or cytoplasmic microtubules and actin filaments, kinesin or myosin motor proteins, the nuclear envelope, various nuclear compartments, chromosome topology, chromatin loop extrusion and diverse signalling cues. These processes are commonly altered in cancer and during natural or premature ageing. Indeed, the reshaping of the genome in nuclear space during DSB repair points to new avenues for therapeutic interventions that may take advantage of new cancer cell vulnerabilities or aim to reverse age-associated defects.
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Affiliation(s)
- Irene Chiolo
- Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, USA.
| | - Matthias Altmeyer
- Department of Molecular Mechanisms of Disease, University of Zurich (UZH), Zurich, Switzerland.
| | - Gaëlle Legube
- MCD, Centre de Biologie Intégrative (CBI), CNRS, Université de Toulouse, UT3, Toulouse, France.
| | - Karim Mekhail
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
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2
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Kwak H, Lee E, Karki R. DNA sensors in metabolic and cardiovascular diseases: Molecular mechanisms and therapeutic prospects. Immunol Rev 2025; 329:e13382. [PMID: 39158380 PMCID: PMC11744256 DOI: 10.1111/imr.13382] [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] [Indexed: 08/20/2024]
Abstract
DNA sensors generally initiate innate immune responses through the production of type I interferons. While extensively studied for host defense against invading pathogens, emerging evidence highlights the involvement of DNA sensors in metabolic and cardiovascular diseases. Elevated levels of modified, damaged, or ectopically localized self-DNA and non-self-DNA have been observed in patients and animal models with obesity, diabetes, fatty liver disease, and cardiovascular disease. The accumulation of cytosolic DNA aberrantly activates DNA signaling pathways, driving the pathological progression of these disorders. This review highlights the roles of specific DNA sensors, such as cyclic AMP-GMP synthase and stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9), interferon gamma-inducible protein 16 (IFI16), DNA-dependent protein kinase (DNA-PK), and DEAD-box helicase 41 (DDX41) in various metabolic disorders. We explore how DNA signaling pathways in both immune and non-immune cells contribute to the development of these diseases. Furthermore, we discuss the intricate interplay between metabolic stress and immune responses, offering insights into potential therapeutic targets for managing metabolic and cardiovascular disorders. Understanding the mechanisms of DNA sensor signaling in these contexts provides a foundation for developing novel interventions aimed at mitigating the impact of these pervasive health issues.
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Affiliation(s)
- Hyosang Kwak
- Department of Biological Sciences, College of Natural ScienceSeoul National UniversitySeoulSouth Korea
| | - Ein Lee
- Department of Biomedical Sciences, College of MedicineSeoul National UniversitySeoulSouth Korea
| | - Rajendra Karki
- Department of Biological Sciences, College of Natural ScienceSeoul National UniversitySeoulSouth Korea
- Nexus Institute of Research and Innovation (NIRI)KathmanduNepal
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3
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Camfield S, Chakraborty S, Dwivedi SKD, Pramanik PK, Mukherjee P, Bhattacharya R. Secrets of DNA-PKcs beyond DNA repair. NPJ Precis Oncol 2024; 8:154. [PMID: 39043779 PMCID: PMC11266574 DOI: 10.1038/s41698-024-00655-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 07/15/2024] [Indexed: 07/25/2024] Open
Abstract
The canonical role of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in repairing DNA double-strand breaks combined with its reported dysregulation in several malignancies has driven the development of DNA-PKcs inhibitors as therapeutics. However, until recently the relationship between DNA-PKcs and tumorigenesis has been primarily investigated with regard to its role in non-homologous end joining (NHEJ) repair. Emerging research has uncovered non-canonical DNA-PKcs functions involved with transcriptional regulation, telomere maintenance, metabolic regulation, and immune signaling all of which may also impinge on tumorigenesis. This review mainly discusses these non-canonical roles of DNA-PKcs in cellular biology and their potential contribution to tumorigenesis, as well as evaluating the implications of targeting DNA-PKcs for cancer therapy.
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Affiliation(s)
- Sydney Camfield
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Sayan Chakraborty
- Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Shailendra Kumar Dhar Dwivedi
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Pijush Kanti Pramanik
- Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Priyabrata Mukherjee
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Resham Bhattacharya
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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4
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Wu J, Song L, Lu M, Gao Q, Xu S, Zhou P, Ma T. The multifaceted functions of DNA-PKcs: implications for the therapy of human diseases. MedComm (Beijing) 2024; 5:e613. [PMID: 38898995 PMCID: PMC11185949 DOI: 10.1002/mco2.613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 05/07/2024] [Accepted: 05/09/2024] [Indexed: 06/21/2024] Open
Abstract
The DNA-dependent protein kinase (DNA-PK), catalytic subunit, also known as DNA-PKcs, is complexed with the heterodimer Ku70/Ku80 to form DNA-PK holoenzyme, which is well recognized as initiator in the nonhomologous end joining (NHEJ) repair after double strand break (DSB). During NHEJ, DNA-PKcs is essential for both DNA end processing and end joining. Besides its classical function in DSB repair, DNA-PKcs also shows multifaceted functions in various biological activities such as class switch recombination (CSR) and variable (V) diversity (D) joining (J) recombination in B/T lymphocytes development, innate immunity through cGAS-STING pathway, transcription, alternative splicing, and so on, which are dependent on its function in NHEJ or not. Moreover, DNA-PKcs deficiency has been proven to be related with human diseases such as neurological pathogenesis, cancer, immunological disorder, and so on through different mechanisms. Therefore, it is imperative to summarize the latest findings about DNA-PKcs and diseases for better targeting DNA-PKcs, which have shown efficacy in cancer treatment in preclinical models. Here, we discuss the multifaceted roles of DNA-PKcs in human diseases, meanwhile, we discuss the progresses of DNA-PKcs inhibitors and their potential in clinical trials. The most updated review about DNA-PKcs will hopefully provide insights and ideas to understand DNA-PKcs associated diseases.
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Affiliation(s)
- Jinghong Wu
- Cancer Research CenterBeijing Chest HospitalCapital Medical University/Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingChina
| | - Liwei Song
- Department of Thoracic SurgeryBeijing Chest HospitalCapital Medical University, Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingChina
| | - Mingjun Lu
- Cancer Research CenterBeijing Chest HospitalCapital Medical University/Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingChina
| | - Qing Gao
- Cancer Research CenterBeijing Chest HospitalCapital Medical University/Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingChina
| | - Shaofa Xu
- Department of Thoracic SurgeryBeijing Chest HospitalCapital Medical University, Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingChina
| | - Ping‐Kun Zhou
- Beijing Key Laboratory for RadiobiologyBeijing Institute of Radiation MedicineBeijingChina
| | - Teng Ma
- Cancer Research CenterBeijing Chest HospitalCapital Medical University/Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingChina
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5
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Jubelin C, Muñoz-Garcia J, Ollivier E, Cochonneau D, Vallette F, Heymann MF, Oliver L, Heymann D. Identification of MCM4 and PRKDC as new regulators of osteosarcoma cell dormancy based on 3D cell cultures. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119660. [PMID: 38216092 DOI: 10.1016/j.bbamcr.2024.119660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 12/15/2023] [Accepted: 01/03/2024] [Indexed: 01/14/2024]
Abstract
Dormancy is a potential way for tumors to develop drug resistance and escape treatment. However, the mechanisms involved in cancer dormancy remain poorly understood. This is mainly because there is no in vitro culture model making it possible to spontaneously induce dormancy. In this context, the present work proposes the use of three-dimensional (3D) spheroids developed from osteosarcoma cell lines as a relevant model for studying cancer dormancy. MNNG-HOS, SaOS-2, 143B, MG-63, U2OS and SJSA-1 cell lines were cultured in 3D using the Liquid Overlay Technique (LOT). Dormancy was studied by staining cancer cells with a lipophilic dye (DiD), and long-term DiD+ cells were considered as dormant cancer cells. The role of the extracellular matrix in inducing dormancy was investigated by embedding cells into methylcellulose or Geltrex™. Gene expression of DiD+ cells was assessed with a Nanostring™ approach and the role of the genes detected in dormancy was validated by a transient down-expression model using siRNA treatment. Proliferation was measured using fluorescence microscopy and the xCELLigence technology. We observed that MNNG-HOS, 143B and MG-G3 cell lines had a reduced proliferation rate in 3D compared to 2D. U2OS cells had an increased proliferation rate when they were cultured in Geltrex™ compared to other 3D culture methods. Using 3D cultures, a transcriptomic signature of dormancy was obtained and showed a decreased expression of 18 genes including ETV4, HELLS, ITGA6, MCM4, PRKDC, RAD21 and UBE2T. The treatment with siRNA targeting these genes showed that cancer cell proliferation was reduced when the expression of ETV4 and MCM4 were decreased, whereas proliferation was increased when the expression of RAD21 was decreased. 3D culture facilitates the maintenance of dormant cancer cells characterized by a reduced proliferation and less differential gene expression as compared to proliferative cells. Further studies of the genes involved has enabled us to envisage their role in regulating cell proliferation.
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Affiliation(s)
- Camille Jubelin
- Nantes Université, CNRS, US2B, UMR 6286, 44000 Nantes, France; Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Lab., 44805 Saint-Herblain, France; Atlantic Bone Screen, 44800 Saint-Herblain, France
| | - Javier Muñoz-Garcia
- Nantes Université, CNRS, US2B, UMR 6286, 44000 Nantes, France; Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Lab., 44805 Saint-Herblain, France
| | - Emilie Ollivier
- Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Lab., 44805 Saint-Herblain, France
| | - Denis Cochonneau
- Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Lab., 44805 Saint-Herblain, France
| | - François Vallette
- Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Lab., 44805 Saint-Herblain, France; Nantes Université, INSERM, CRCI(2)NA, UMR1307, 44000 Nantes, France
| | - Marie-Françoise Heymann
- Nantes Université, CNRS, US2B, UMR 6286, 44000 Nantes, France; Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Lab., 44805 Saint-Herblain, France
| | - Lisa Oliver
- Nantes Université, INSERM, CRCI(2)NA, UMR1307, 44000 Nantes, France; CHU de Nantes, Nantes, France
| | - Dominique Heymann
- Nantes Université, CNRS, US2B, UMR 6286, 44000 Nantes, France; Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Lab., 44805 Saint-Herblain, France; Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK.
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Chen Y, Zhen Z, Chen L, Wang H, Wang X, Sun X, Song Z, Wang H, Lin Y, Zhang W, Wu G, Jiang Y, Mao Z. Androgen signaling stabilizes genomes to counteract senescence by promoting XRCC4 transcription. EMBO Rep 2023; 24:e56984. [PMID: 37955230 PMCID: PMC10702805 DOI: 10.15252/embr.202356984] [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: 02/13/2023] [Revised: 10/16/2023] [Accepted: 10/24/2023] [Indexed: 11/14/2023] Open
Abstract
Aging is accompanied by a decreased DNA repair capacity, which might contribute to age-associated functional decline in multiple tissues. Disruption in hormone signaling, associated with reproductive organ dysfunction, is an early event of age-related tissue degeneration, but whether it impacts DNA repair in nonreproductive organs remains elusive. Using skin fibroblasts derived from healthy donors with a broad age range, we show here that the downregulation of expression of XRCC4, a factor involved in nonhomologous end-joining (NHEJ) repair, which is the dominant pathway to repair somatic double-strand breaks, is mediated through transcriptional mechanisms. We show that the androgen receptor (AR), whose expression is also reduced during aging, directly binds to and enhances the activity of the XRCC4 promoter, facilitating XRCC4 transcription and thus stabilizing the genome. We also demonstrate that dihydrotestosterone (DHT), a powerful AR agonist, restores XRCC4 expression and stabilizes the genome in different models of cellular aging. Moreover, DHT treatment reverses senescence-associated phenotypes, opening a potential avenue to aging interventions in the future.
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Affiliation(s)
- Yu Chen
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zhengyi Zhen
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Lingjiang Chen
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Hao Wang
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xuhui Wang
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xiaoxiang Sun
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zhiwei Song
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Haiyan Wang
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yizi Lin
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Wenjun Zhang
- Department of Plastic Surgery, Changzheng Hospital, Shanghai, China
| | - Guizhu Wu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Shanghai Tongji University School of Medicine, Shanghai, China
| | - Ying Jiang
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zhiyong Mao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
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7
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Choi W, Lee ES. Therapeutic Targeting of DNA Damage Response in Cancer. Int J Mol Sci 2022; 23:ijms23031701. [PMID: 35163621 PMCID: PMC8836062 DOI: 10.3390/ijms23031701] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/25/2022] [Accepted: 01/29/2022] [Indexed: 02/07/2023] Open
Abstract
DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.
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Affiliation(s)
- Wonyoung Choi
- Research Institute, National Cancer Center, Goyang 10408, Korea;
- Center for Clinical Trials, National Cancer Center, Goyang 10408, Korea
| | - Eun Sook Lee
- Research Institute, National Cancer Center, Goyang 10408, Korea;
- Center for Breast Cancer, National Cancer Center, Goyang 10408, Korea
- Correspondence: ; Tel.: +82-31-920-1633
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8
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Yoshioka KI, Kusumoto-Matsuo R, Matsuno Y, Ishiai M. Genomic Instability and Cancer Risk Associated with Erroneous DNA Repair. Int J Mol Sci 2021; 22:12254. [PMID: 34830134 PMCID: PMC8625880 DOI: 10.3390/ijms222212254] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 12/23/2022] Open
Abstract
Many cancers develop as a consequence of genomic instability, which induces genomic rearrangements and nucleotide mutations. Failure to correct DNA damage in DNA repair defective cells, such as in BRCA1 and BRCA2 mutated backgrounds, is directly associated with increased cancer risk. Genomic rearrangement is generally a consequence of erroneous repair of DNA double-strand breaks (DSBs), though paradoxically, many cancers develop in the absence of DNA repair defects. DNA repair systems are essential for cell survival, and in cancers deficient in one repair pathway, other pathways can become upregulated. In this review, we examine the current literature on genomic alterations in cancer cells and the association between these alterations and DNA repair pathway inactivation and upregulation.
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Affiliation(s)
- Ken-ichi Yoshioka
- Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (R.K.-M.); (Y.M.)
| | - Rika Kusumoto-Matsuo
- Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (R.K.-M.); (Y.M.)
| | - Yusuke Matsuno
- Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (R.K.-M.); (Y.M.)
- Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
| | - Masamichi Ishiai
- Central Radioisotope Division, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan;
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Swift ML, Sell C, Azizkhan-Clifford J. DNA damage-induced degradation of Sp1 promotes cellular senescence. GeroScience 2021; 44:683-698. [PMID: 34550526 PMCID: PMC9135943 DOI: 10.1007/s11357-021-00456-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/07/2021] [Indexed: 11/28/2022] Open
Abstract
Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. Sp1 has been found to play a role in double strand break (DSB) repair, and a link between Sp1 and aging has also been established, where Sp1 protein, but not RNA, levels decrease with age. Interestingly, inhibition ATM reverses the age-related degradation of Sp1, suggesting that DNA damage signaling is involved in senescence-related degradation of Sp1. Proteasomal degradation of Sp1 in senescent cells is mediated via sumoylation, where sumoylation of Sp1 on lysine 16 is increased in senescent cells. Taking into consideration our previous findings that Sp1 is phosphorylated by ATM in response to DNA damage and that proteasomal degradation of Sp1 at DSBs is also mediated by its sumoylation and subsequent interaction with RNF4, we investigated the potential contribution of Sp1’s role as a DSB repair factor in mediating cellular senescence. We report here that Sp1 expression is decreased with a concomitant increase in senescence markers in response to DNA damage. Mutation of Sp1 at serine 101 to create an ATM phospho-null mutant, or mutation of lysine 16 to create a sumo-null mutant, prevents the sumoylation and subsequent proteasomal degradation of Sp1 and results in a decrease in senescence. Conversely, depletion of Sp1 or mutation of Sp1 to create an ATM phosphomimetic results in premature degradation of Sp1 and an increase in senescence markers. These data link a loss of genomic stability with senescence through the action of a DNA damage repair factor.
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Affiliation(s)
- Michelle L Swift
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N 15th Street, MS497, Philadelphia, PA, 19102, USA
| | - Christian Sell
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N 15th Street, MS497, Philadelphia, PA, 19102, USA
| | - Jane Azizkhan-Clifford
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N 15th Street, MS497, Philadelphia, PA, 19102, USA.
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10
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Barros PR, Costa TJ, Akamine EH, Tostes RC. Vascular Aging in Rodent Models: Contrasting Mechanisms Driving the Female and Male Vascular Senescence. FRONTIERS IN AGING 2021; 2:727604. [PMID: 35821995 PMCID: PMC9261394 DOI: 10.3389/fragi.2021.727604] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022]
Abstract
Increasing scientific interest has been directed to sex as a biological and decisive factor on several diseases. Several different mechanisms orchestrate vascular function, as well as vascular dysfunction in cardiovascular and metabolic diseases in males and females. Certain vascular sex differences are present throughout life, while others are more evident before the menopause, suggesting two important and correlated drivers: genetic and hormonal factors. With the increasing life expectancy and aging population, studies on aging-related diseases and aging-related physiological changes have steeply grown and, with them, the use of aging animal models. Mouse and rat models of aging, the most studied laboratory animals in aging research, exhibit sex differences in many systems and physiological functions, as well as sex differences in the aging process and aging-associated cardiovascular changes. In the present review, we introduce the most common aging and senescence-accelerated animal models and emphasize that sex is a biological variable that should be considered in aging studies. Sex differences in the cardiovascular system, with a focus on sex differences in aging-associated vascular alterations (endothelial dysfunction, remodeling and oxidative and inflammatory processes) in these animal models are reviewed and discussed.
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Affiliation(s)
- Paula R. Barros
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Tiago J. Costa
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Eliana H. Akamine
- Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
- *Correspondence: Rita C. Tostes, ; Eliana H. Akamine,
| | - Rita C. Tostes
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- *Correspondence: Rita C. Tostes, ; Eliana H. Akamine,
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11
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Goff PH, Bhakuni R, Pulliam T, Lee JH, Hall ET, Nghiem P. Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer? Cancers (Basel) 2021; 13:3415. [PMID: 34298632 PMCID: PMC8307089 DOI: 10.3390/cancers13143415] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/19/2022] Open
Abstract
Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers.
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Affiliation(s)
- Peter H. Goff
- Department of Radiation Oncology, University of Washington, Seattle, WA 98195, USA;
| | - Rashmi Bhakuni
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, USA; (R.B.); (T.P.); (J.H.L.)
| | - Thomas Pulliam
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, USA; (R.B.); (T.P.); (J.H.L.)
| | - Jung Hyun Lee
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, USA; (R.B.); (T.P.); (J.H.L.)
- Institute for Stem Cell and Regenerative Medicine, Department of Bioengineering, University of Washington, Seattle, WA 98109, USA
| | - Evan T. Hall
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA 98109, USA;
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Paul Nghiem
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, USA; (R.B.); (T.P.); (J.H.L.)
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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12
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Hu S, Hui Z, Lirussi F, Garrido C, Ye XY, Xie T. Small molecule DNA-PK inhibitors as potential cancer therapy: a patent review (2010-present). Expert Opin Ther Pat 2021; 31:435-452. [PMID: 33347360 DOI: 10.1080/13543776.2021.1866540] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: DNA-dependent protein kinase (DNA-PK) plays a crucial role in the repair of DSBs via non-homologous end joining (NHEJ). Several DNA-PK inhibitors are being investigated for potential anticancer treatment in clinical trials.Area covered: This review aims to give an overview of patents published since 2010 by analyzing the patent space and structure features of scaffolds used in those patents. It also discusses the recent clinical developments and provides perspectives on future challenges and directions in this field.Expert opinion: As a key component of the DNA damage response (DDR) pathway, DNA-PK appears to be a viable drug target for anticancer therapy. The clinical investigation of a DNA-PK inhibitor employs both a monotherapy and a combination strategy. In the combination strategy, a DNA-PK inhibitor is typically combined with a DSB inducer, radiation, a chemotherapy agent, or a PARP inhibitor, etc. Patent analyses suggest that diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl are capable to achieve good DNA-PK inhibitory activity and good DNA-PK selectivity over other closely related enzymes. Several DNA-PK inhibitors are currently being evaluated in clinics, with the hope to get approval in the near future.
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Affiliation(s)
- Suwen Hu
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, Zhejiang, People's Republic of China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Zhejiang Province, People's Republic of China.,;cCollaborative Innovation Center of Chinese Medicines from Zhejiang Province, Zhejiang Province, People's Republic of China.,;dKey Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang Province, People's Republic of China.,;eHangzhou Huadong Medicine Group, Pharmaceutical Research Institute Co. Ltd, Hanzhou City, Zhejiang Province, People's Republic of China
| | - Zi Hui
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, Zhejiang, People's Republic of China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Zhejiang Province, People's Republic of China.,;cCollaborative Innovation Center of Chinese Medicines from Zhejiang Province, Zhejiang Province, People's Republic of China.,;Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang Province, People's Republic of China
| | - Frédéric Lirussi
- ;fINSERM, U1231, Label LipSTIC, and Ligue Nationale Contre Le Cancer, Dijon, France.,;gUniversité De Bourgogne-Franche Comté, I-SITE, France.,;hDepartment of Pharmacology-Toxicology & Metabolomics, University hospital of Besançon (CHU), 2 Boulevard Fleming, 25030 BESANCON, France
| | - Carmen Garrido
- ;INSERM, U1231, Label LipSTIC, and Ligue Nationale Contre Le Cancer, Dijon, France.,;Université De Bourgogne-Franche Comté, I-SITE, France.,;iAnti-cancer Center George-François Leclerc, CGFL, Dijon, France
| | - Xiang-Yang Ye
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, Zhejiang, People's Republic of China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Zhejiang Province, People's Republic of China.,;cCollaborative Innovation Center of Chinese Medicines from Zhejiang Province, Zhejiang Province, People's Republic of China.,;Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang Province, People's Republic of China
| | - Tian Xie
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, Zhejiang, People's Republic of China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Zhejiang Province, People's Republic of China.,;cCollaborative Innovation Center of Chinese Medicines from Zhejiang Province, Zhejiang Province, People's Republic of China.,;Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang Province, People's Republic of China
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13
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Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity. Cancers (Basel) 2020; 12:cancers12113389. [PMID: 33207636 PMCID: PMC7698146 DOI: 10.3390/cancers12113389] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/10/2020] [Accepted: 11/12/2020] [Indexed: 01/07/2023] Open
Abstract
The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key component of the DNA-PK complex that has a well-characterized function in the non-homologous end-joining repair of DNA double-strand breaks. Since its identification, a large body of evidence has demonstrated that DNA-PKcs is frequently overexpressed in cancer, plays a critical role in tumor development and progression, and is associated with poor prognosis of cancer patients. Intriguingly, recent studies have suggested novel functions beyond the canonical role of DNA-PKcs, which has transformed the paradigm of DNA-PKcs in tumorigenesis and has reinvigorated the interest to target DNA-PKcs for cancer treatment. In this review, we update recent advances in DNA-PKcs, in particular the emerging roles in tumor metastasis, metabolic dysregulation, and immune escape. We further discuss the possible molecular basis that underpins the pleiotropism of DNA-PKcs in cancer. Finally, we outline the biomarkers that may predict the therapeutic response to DNA-PKcs inhibitor therapy. Understanding the functional repertoire of DNA-PKcs will provide mechanistic insights of DNA-PKcs in malignancy and, more importantly, may revolutionize the design and utility of DNA-PKcs-based precision cancer therapy.
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14
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DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions. Pharmacol Ther 2020; 215:107617. [PMID: 32610116 DOI: 10.1016/j.pharmthera.2020.107617] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/15/2020] [Indexed: 12/12/2022]
Abstract
The DNA-PK holoenzyme is a fundamental element of the DNA damage response machinery (DDR), which is responsible for cellular genomic stability. Consequently, and predictably, over the last decades since its identification and characterization, numerous pre-clinical and clinical studies reported observations correlating aberrant DNA-PK status and activity with cancer onset, progression and responses to therapeutic modalities. Notably, various studies have established in recent years the role of DNA-PK outside the DDR network, corroborating its role as a pleiotropic complex involved in transcriptional programs that operate biologic processes as epithelial to mesenchymal transition (EMT), hypoxia, metabolism, nuclear receptors signaling and inflammatory responses. In particular tumor entities as prostate cancer, immense research efforts assisted mapping and describing the overall signaling networks regulated by DNA-PK that control metastasis and tumor progression. Correspondingly, DNA-PK emerges as an obvious therapeutic target in cancer and data pertaining to various pharmacological approaches have been published, largely in context of combination with DNA-damaging agents (DDAs) that act by inflicting DNA double strand breaks (DSBs). Currently, new generation inhibitors are tested in clinical trials. Several excellent reviews have been published in recent years covering the biology of DNA-PK and its role in cancer. In the current article we are aiming to systematically describe the main findings on DNA-PK signaling in major cancer types, focusing on both preclinical and clinical reports and present a detailed current status of the DNA-PK inhibitors repertoire.
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15
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Abstract
DNA-dependent protein kinase (DNA-PK) is involved in many cellular pathways. It has a key role in the cellular response to DNA damage, in the repair of DNA double-strand break (DNA-DSBs) and as a consequence an important role in maintaining genomic integrity. In addition, DNA-PK has been shown to modulate transcription, to be involved in the development of the immune system and to protect telomeres. These pleotropic involvements and the fact that its expression is de-regulated in cancer have made DNA-PK an intriguing therapeutic target in cancer therapy, especially when combined with agents causing DNA-DSBs such as topoisomerase II inhibitors and ionizing radiation. Different small molecule inhibitors of DNA-PK have been recently synthesized and some are now being tested in clinical trials. This review discusses what is known about DNA-PK, its role in tumor biology, DNA repair and cancer therapy and critically discusses its inhibition as a potential therapeutic approach.
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Affiliation(s)
- Giovanna Damia
- Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy.
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16
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Zhang H, Cai B, Geng A, Tang H, Zhang W, Li S, Jiang Y, Tan R, Wan X, Mao Z. Base excision repair but not DNA double-strand break repair is impaired in aged human adipose-derived stem cells. Aging Cell 2020; 19:e13062. [PMID: 31782607 PMCID: PMC6996963 DOI: 10.1111/acel.13062] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 08/21/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023] Open
Abstract
The decline in DNA repair capacity contributes to the age-associated decrease in genome integrity in somatic cells of different species. However, due to the lack of clinical samples and appropriate tools for studying DNA repair, whether and how age-associated changes in DNA repair result in a loss of genome integrity of human adult stem cells remains incompletely characterized. Here, we isolated 20 eyelid adipose-derived stem cell (ADSC) lines from healthy individuals (young: 10 donors with ages ranging 17-25 years; old: 10 donors with ages ranging 50-59 years). Using these cell lines, we systematically compared the efficiency of base excision repair (BER) and two DNA double-strand break (DSB) repair pathways-nonhomologous end joining (NHEJ) and homologous recombination (HR)-between the young and old groups. Surprisingly, we found that the efficiency of BER but not NHEJ or HR is impaired in aged human ADSCs, which is in contrast to previous findings that DSB repair declines with age in human fibroblasts. We also demonstrated that BER efficiency is negatively associated with tail moment, which reflects a loss of genome integrity in human ADSCs. Mechanistic studies indicated that at the protein level XRCC1, but not other BER factors, exhibited age-associated decline. Overexpression of XRCC1 reversed the decline of BER efficiency and genome integrity, indicating that XRCC1 is a potential therapeutic target for stabilizing genomes in aged ADSCs.
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Affiliation(s)
- Haiping Zhang
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Bailian Cai
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Anke Geng
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Huanyin Tang
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Wenjun Zhang
- Department of Plastic SurgeryChangzheng HospitalShanghaiChina
| | - Sheng Li
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Ying Jiang
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Rong Tan
- Center for Molecular MedicineXiangya HospitalCentral South UniversityChangshaChina
| | - Xiaoping Wan
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Zhiyong Mao
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
- Clinical and Translational Research Center of Shanghai First Maternity & Infant HospitalSchool of MedicineTongji UniversityShanghaiChina
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
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17
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Folgueras AR, Freitas-Rodríguez S, Velasco G, López-Otín C. Mouse Models to Disentangle the Hallmarks of Human Aging. Circ Res 2019; 123:905-924. [PMID: 30355076 DOI: 10.1161/circresaha.118.312204] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Model organisms have provided fundamental evidence that aging can be delayed and longevity extended. These findings gave rise to a new era in aging research aimed at elucidating the pathways and networks controlling this complex biological process. The identification of 9 hallmarks of aging has established a framework to evaluate the relative contribution of each hallmark and the interconnections among them. In this review, we revisit these hallmarks with the information obtained exclusively through the generation of genetically modified mouse models that have a significant impact on the aging process. We discuss within each hallmark those interventions that accelerate aging or that have been successful at increasing lifespan, with the final goal of identifying the most promising antiaging avenues based on the current knowledge provided by in vivo models.
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Affiliation(s)
- Alicia R Folgueras
- From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Spain
| | - Sandra Freitas-Rodríguez
- From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Spain
| | - Gloria Velasco
- From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Spain
| | - Carlos López-Otín
- From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Spain
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18
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Cancer risk from low dose radiation in Ptch1/ mice with inactive DNA repair systems: Therapeutic implications for medulloblastoma. DNA Repair (Amst) 2019; 74:70-79. [DOI: 10.1016/j.dnarep.2018.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 12/03/2018] [Accepted: 12/14/2018] [Indexed: 12/14/2022]
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19
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Lu Y, Tao F, Zhou MT, Tang KF. The signaling pathways that mediate the anti-cancer effects of caloric restriction. Pharmacol Res 2019; 141:512-520. [PMID: 30641278 DOI: 10.1016/j.phrs.2019.01.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/31/2018] [Accepted: 01/11/2019] [Indexed: 02/07/2023]
Abstract
Caloric restriction (CR) has been shown to promote longevity and ameliorate aging-associated diseases, including cancer. Extensive research over recent decades has revealed that CR reduces IGF-1/PI3K/AKT signaling and increases sirtuin signaling. We recently found that CR also enhances ALDOA/DNA-PK/p53 signaling. In the present review, we summarize the molecular mechanisms underlying the modulation of the IGF-1/PI3K/AKT pathway, sirtuin signaling, and the ALDOA/DNA-PK/p53 pathway by CR. We also summarize the evidence concerning the roles of these signaling pathways in carcinogenesis, and discuss how they are regulated by CR. Finally, we discuss the crosstalk between these signaling pathways.
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Affiliation(s)
- Yiyi Lu
- Department of Dermato-Venereology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China
| | - Fengxing Tao
- Department of Dermato-Venereology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China
| | - Meng-Tao Zhou
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
| | - Kai-Fu Tang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China; Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
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20
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Sifuentes-Franco S, Carrillo-Ibarra S, Miranda-Díaz AG, Cerrillos-Gutíerrez JI, Escalante-Núñez A, Andrade-Sierra J, Villanueva-Pérez MA, Rojas-Campos E, Reyes-Estrada CA. Systemic Expression of Oxidative DNA Damage and Apoptosis Markers in Acute Renal Graft Dysfunction. EUROPEAN MEDICAL JOURNAL 2018. [DOI: 10.33590/emj/10313015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
Background: Acute renal graft dysfunction (AGD) is one of the primary complications after kidney transplantation. The aim of this study was to identify the systemic oxidative DNA damage and apoptosis markers in patients with AGD, which will aid the understanding of the underlying processes of the complication.
Methods: A cross-sectional analytical study was conducted in renal transplant (RT) recipients with and without AGD. The follow-up time of patients was <1 year. Using the ELISA technique, the markers of oxidative DNA damage (8-hydroxy-2-deoxyguanosine and 8-oxoguanine-DNA-N-glycosylase-1) and apoptosis (caspase-3, caspase-8, soluble TNF receptor 1, and cytochrome C) were determined.
Results: Donor age was significantly higher in patients with AGD versus those without AGD (43±11 years versus 34.1±10.6 years, respectively; p<0.001). Levels of 8-hydroxy-2-deoxyguanosine were also significantly higher in AGD patients than those without AGD (624.1±15.3 ng/mL and 563.02± 17.4 ng/mL, respectively; p=0.039) and the DNA repair enzyme 8-oxoguanine-DNA-N-glycosylase-1 was significantly diminished in AGD patients versus non-AGD patients (7.60±1.8 ng/mL versus 8.13±1.70 ng/mL, respectively; p=0.031). A significant elevation of soluble TNF receptor levels in AGD patients was also found versus those without AGD (1178.6±25.2 ng/mL versus 142.6±39 ng/mL, respectively; p=0.03). Caspase-3 levels were higher in patients with AGD (1.19±0.21 ng/mL) versus those without AGD (0.79±0.11 ng/mL; p=0.121) and was also significantly augmented in AGD versus healthy control subjects (0.24±0.1 ng/mL; p=0.036). Cytochrome c in AGD patients was 0.32±0.09 ng/mL and 0.16±0.03 ng/mL in those without AGD versus 0.08±0.01 ng/mL in healthy controls (p=0.130 and p=0.184, respectively).
Conclusion: These findings suggest that oxidative DNA damage with insufficient DNA repair and higher levels of caspase-3 compared to controls are markers of apoptosis protein dysregulation in AGD patients.
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Affiliation(s)
- Sonia Sifuentes-Franco
- Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Health Sciences Centre, University of Guadalajara, Guadalajara, Mexico
| | - Sandra Carrillo-Ibarra
- Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Health Sciences Centre, University of Guadalajara, Guadalajara, Mexico
| | - Alejandra Guillermina Miranda-Díaz
- Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Health Sciences Centre, University of Guadalajara, Guadalajara, Mexico
| | - José Ignacio Cerrillos-Gutíerrez
- Department of Nephrology and Transplants, Specialties Hospital, National Occidental Medical Centre, Mexican Social Security Institute, Guadalajara, Mexico
| | - Ariadna Escalante-Núñez
- Department of Nephrology and Transplants, Specialties Hospital, National Occidental Medical Centre, Mexican Social Security Institute, Guadalajara, Mexico
| | - Jorge Andrade-Sierra
- Department of Nephrology and Transplants, Specialties Hospital, National Occidental Medical Centre, Mexican Social Security Institute, Guadalajara, Mexico
| | - Martha Arisbeth Villanueva-Pérez
- Department of Nephrology and Transplants, Specialties Hospital, National Occidental Medical Centre, Mexican Social Security Institute, Guadalajara, Mexico
| | - Enrique Rojas-Campos
- Kidney Diseases Medical Research Unit, Specialties Hospital, National Occidental Medical Centre, Mexican Social Security Institute, Guadalajara, Mexico
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Genomic Approach to Understand the Association of DNA Repair with Longevity and Healthy Aging Using Genomic Databases of Oldest-Old Population. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:2984730. [PMID: 29854078 PMCID: PMC5960555 DOI: 10.1155/2018/2984730] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Accepted: 04/03/2018] [Indexed: 12/16/2022]
Abstract
Aged population is increasing worldwide due to the aging process that is inevitable. Accordingly, longevity and healthy aging have been spotlighted to promote social contribution of aged population. Many studies in the past few decades have reported the process of aging and longevity, emphasizing the importance of maintaining genomic stability in exceptionally long-lived population. Underlying reason of longevity remains unclear due to its complexity involving multiple factors. With advances in sequencing technology and human genome-associated approaches, studies based on population-based genomic studies are increasing. In this review, we summarize recent longevity and healthy aging studies of human population focusing on DNA repair as a major factor in maintaining genome integrity. To keep pace with recent growth in genomic research, aging- and longevity-associated genomic databases are also briefly introduced. To suggest novel approaches to investigate longevity-associated genetic variants related to DNA repair using genomic databases, gene set analysis was conducted, focusing on DNA repair- and longevity-associated genes. Their biological networks were additionally analyzed to grasp major factors containing genetic variants of human longevity and healthy aging in DNA repair mechanisms. In summary, this review emphasizes DNA repair activity in human longevity and suggests approach to conduct DNA repair-associated genomic study on human healthy aging.
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22
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Chung JH. The role of DNA-PK in aging and energy metabolism. FEBS J 2018; 285:1959-1972. [PMID: 29453899 DOI: 10.1111/febs.14410] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 01/15/2018] [Accepted: 02/12/2018] [Indexed: 12/17/2022]
Abstract
DNA-dependent protein kinase (DNA-PK) is a very large holoenzyme comprised of the p470 kDa DNA-PK catalytic subunit (DNA-PKcs ) and the Ku heterodimer consisting of the p86 (Ku 80) and p70 (Ku 70) subunits. It is best known for its nonhomologous end joining (NHEJ) activity, which repairs double-strand DNA (dsDNA) breaks (DSBs). As expected, the absence of DNA-PK activity results in sensitivity to ionizing radiation, which generates DSBs and defect in lymphocyte development, which requires NHEJ of the V(D)J region in the immunoglobulin and T-cell receptor loci. DNA-PK also has been reported to have functions seemingly unrelated to NHEJ. For example, DNA-PK responds to insulin signaling to facilitate the conversion of carbohydrates to fatty acids in the liver. More recent evidence indicates that DNA-PK activity increases with age in skeletal muscle, promoting mitochondrial loss and weight gain. These discoveries suggest that our understanding of DNA-PK is far from complete. As many excellent reviews have already been written about the role of DNA-PK in NHEJ, here we will review the non-NHEJ role of DNA-PK with a focus on its role in aging and energy metabolism.
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Affiliation(s)
- Jay H Chung
- Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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23
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Han J, Tang FM, Pu D, Xu D, Wang T, Li W. Mechanisms Underlying Regulation of Cell Cycle and Apoptosis by hnRNP B1 in Human Lung Adenocarcinoma A549 Cells. TUMORI JOURNAL 2018. [DOI: 10.1177/1430.15824] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Juan Han
- Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Feng-ming Tang
- Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Dan Pu
- Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Dan Xu
- Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Tao Wang
- Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Weimin Li
- Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
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Abstract
Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease. Immune system aging functions as an accelerator for other age-related pathologies. It occurs prematurely in some clinical conditions, most prominently in patients with the autoimmune syndrome rheumatoid arthritis (RA); and such patients serve as an informative model system to study molecular mechanisms of immune aging. T cells from patients with RA are prone to differentiate into proinflammatory effector cells, sustaining chronic-persistent inflammatory lesions in the joints and many other organ systems. RA T cells have several hallmarks of cellular aging; most importantly, they accumulate damaged DNA. Because of deficiency of the DNA repair kinase ataxia telangiectasia mutated, RA T cells carry a higher burden of DNA double-strand breaks, triggering cell-indigenous stress signals that shift the cell's survival potential and differentiation pattern. Immune aging in RA T cells is also associated with metabolic reprogramming; specifically, with reduced glycolytic flux and diminished ATP production. Chronic energy stress affects the longevity and the functional differentiation of older T cells. Altered metabolic patterns provide opportunities to therapeutically target the immune aging process through metabolic interference.
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25
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Gunes C, Avila AI, Rudolph KL. Telomeres in cancer. Differentiation 2017; 99:41-50. [PMID: 29291448 DOI: 10.1016/j.diff.2017.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 12/19/2017] [Accepted: 12/20/2017] [Indexed: 02/07/2023]
Abstract
Telomere shortening as a consequence of cell divisions during aging and chronic diseases associates with an increased cancer risk. Experimental data revealed that telomere shortening results in telomere dysfunction, which in turn affects tumorigenesis in two ways. First, telomere dysfunction suppresses tumor progression by the activation of DNA damage checkpoints, which induce cell cycle arrest (senescence) or apoptosis, as well as by inducing metabolic compromise and activation of immune responses directed against senescent cells. Second, telomere dysfunction promotes tumorigenesis by inducing chromosomal instability in tumor initiating cells, by inhibiting proliferative competition of non-transformed cells, and possibly, also by influencing tumor cell plasticity. The tumor promoting effects of telomere dysfunction are context dependent and require the loss of p53-dependent DNA damage checkpoints or other genetic modifiers that attenuate DNA damage responses possibly involving complex interactions of different genes. The activation of telomere stabilizing mechanisms appears as a subsequent step, which is required to enable immortal grotwh of emerging cancer cells. Here, we conceptually discuss our current knowledge and new, unpublished experimental data on telomere dependent influences on tumor initiation and progression.
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Affiliation(s)
| | - Alush Irene Avila
- Research Group on Stem Cell Aging, Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany
| | - K Lenhard Rudolph
- Research Group on Stem Cell Aging, Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.
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26
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Derevyanko A, Whittemore K, Schneider RP, Jiménez V, Bosch F, Blasco MA. Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span. Aging Cell 2017; 16:1353-1368. [PMID: 28944611 PMCID: PMC5676056 DOI: 10.1111/acel.12677] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2017] [Indexed: 12/18/2022] Open
Abstract
The shelterin complex protects telomeres by preventing them from being degraded and recognized as double‐strand DNA breaks. TRF1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that TRF1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis owing to impaired stem cell function. Here, we show that TRF1 levels decrease during organismal aging both in mice and in humans. We further show that increasing TRF1 expression in both adult (1‐year‐old) and old (2‐year‐old) mice using gene therapy can delay age‐associated pathologies. To this end, we used the nonintegrative adeno‐associated serotype 9 vector (AAV9), which transduces the majority of mouse tissues allowing for moderate and transient TRF1 overexpression. AAV9‐TRF1 gene therapy significantly prevented age‐related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although AAV9‐TRF1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere‐associated DNA damage in some tissues. Together, these findings suggest that rescuing naturally decreased TRF1 levels during mouse aging using AAV9‐TRF1 gene therapy results in an improved mouse health span.
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Affiliation(s)
- Aksinya Derevyanko
- Telomeres and Telomerase Group Molecular Oncology Program Spanish National Cancer Centre (CNIO) Melchor Fernández Almagro 3 Madrid E‐28029 Spain
| | - Kurt Whittemore
- Telomeres and Telomerase Group Molecular Oncology Program Spanish National Cancer Centre (CNIO) Melchor Fernández Almagro 3 Madrid E‐28029 Spain
| | - Ralph P. Schneider
- Telomeres and Telomerase Group Molecular Oncology Program Spanish National Cancer Centre (CNIO) Melchor Fernández Almagro 3 Madrid E‐28029 Spain
| | - Verónica Jiménez
- Center of Animal Biotechnology and Gene Therapy Department of Biochemistry and Molecular Biology School of Veterinary Medicine Universitat Autònoma de Barcelona Bellaterra 08193 Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Madrid Spain
| | - Fàtima Bosch
- Center of Animal Biotechnology and Gene Therapy Department of Biochemistry and Molecular Biology School of Veterinary Medicine Universitat Autònoma de Barcelona Bellaterra 08193 Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Madrid Spain
| | - Maria A. Blasco
- Telomeres and Telomerase Group Molecular Oncology Program Spanish National Cancer Centre (CNIO) Melchor Fernández Almagro 3 Madrid E‐28029 Spain
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27
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The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer. Cancers (Basel) 2017; 9:cancers9070081. [PMID: 28684677 PMCID: PMC5532617 DOI: 10.3390/cancers9070081] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 06/30/2017] [Accepted: 07/03/2017] [Indexed: 12/20/2022] Open
Abstract
DNA double-strand breaks (DSBs) are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect cells from genomic instability. The prominent DSB repair pathway in human cells is the non-homologous end joining (NHEJ) pathway, which mediates template-independent re-ligation of the broken DNA molecule and is active in all phases of the cell cycle. Its role as a guardian of the genome is supported by the fact that defects in NHEJ lead to increased sensitivity to agents that induce DSBs and an increased frequency of chromosomal aberrations. Conversely, evidence from tumors and tumor cell lines has emerged that NHEJ also promotes chromosomal aberrations and genomic instability, particularly in cells that have a defect in one of the other DSB repair pathways. Collectively, the data present a conundrum: how can a single pathway both suppress and promote carcinogenesis? In this review, we will examine NHEJ's role as both a guardian and a disruptor of the genome and explain how underlying genetic context not only dictates whether NHEJ promotes or suppresses carcinogenesis, but also how it alters the response of tumors to conventional therapeutics.
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28
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Zhang T, Zhang Z, Li F, Hu Q, Liu H, Tang M, Ma W, Huang J, Songyang Z, Rong Y, Zhang S, Chen BP, Zhao Y. Looping-out mechanism for resolution of replicative stress at telomeres. EMBO Rep 2017; 18:1412-1428. [PMID: 28615293 DOI: 10.15252/embr.201643866] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 04/29/2017] [Accepted: 05/08/2017] [Indexed: 01/03/2023] Open
Abstract
Repetitive DNA is prone to replication fork stalling, which can lead to genome instability. Here, we find that replication fork stalling at telomeres leads to the formation of t-circle-tails, a new extrachromosomal structure that consists of circular telomeric DNA with a single-stranded tail. Structurally, the t-circle-tail resembles cyclized leading or lagging replication intermediates that are excised from the genome by topoisomerase II-mediated cleavage. We also show that the DNA damage repair machinery NHEJ is required for the formation of t-circle-tails and for the resolution of stalled replication forks, suggesting that NHEJ, which is normally constitutively suppressed at telomeres, is activated in the context of replication stress. Inhibition of NHEJ or knockout of DNA-PKcs impairs telomere replication, leading to multiple-telomere sites (MTS) and telomere shortening. Collectively, our results support a "looping-out" mechanism, in which the stalled replication fork is cut out and cyclized to form t-circle-tails, and broken DNA is religated. The telomere loss induced by replication stress may serve as a new factor that drives replicative senescence and cell aging.
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Affiliation(s)
- Tianpeng Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha, China
| | - Zepeng Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha, China
| | - Feng Li
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qian Hu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha, China
| | - Haiying Liu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha, China
| | - Mengfan Tang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Wenbin Ma
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Junjiu Huang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Zhou Songyang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yikang Rong
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Shichuan Zhang
- Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, China
| | - Benjamin Pc Chen
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yong Zhao
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China .,Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha, China
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29
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Park SJ, Gavrilova O, Brown AL, Soto JE, Bremner S, Kim J, Xu X, Yang S, Um JH, Koch LG, Britton SL, Lieber RL, Philp A, Baar K, Kohama SG, Abel ED, Kim MK, Chung JH. DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging. Cell Metab 2017; 25:1135-1146.e7. [PMID: 28467930 PMCID: PMC5485859 DOI: 10.1016/j.cmet.2017.04.008] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 01/25/2017] [Accepted: 04/11/2017] [Indexed: 12/21/2022]
Abstract
Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function, and decline of physical fitness in middle-aged mice and protects against type 2 diabetes. In conclusion, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, and therefore DNA-PK inhibitors may have therapeutic potential in obesity and low exercise capacity.
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Affiliation(s)
- Sung-Jun Park
- Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Oksana Gavrilova
- Mouse Metabolism Core, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Alexandra L Brown
- Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jamie E Soto
- Program in Molecular Medicine and Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Shannon Bremner
- Department of Orthopedic Surgery, University of California and V.A. Medical Centers, San Diego, La Jolla, CA 92093, USA
| | - Jeonghan Kim
- Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Xihui Xu
- Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shutong Yang
- Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jee-Hyun Um
- Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lauren G Koch
- Department of Anesthesiology, The University of Michigan, Ann Arbor, MI 48109, USA
| | - Steven L Britton
- Department of Anesthesiology, The University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, The University of Michigan, Ann Arbor, MI 48109, USA
| | - Richard L Lieber
- Department of Orthopedic Surgery, University of California and V.A. Medical Centers, San Diego, La Jolla, CA 92093, USA
| | - Andrew Philp
- Department of Physiology and Membrane Biology, University of California Davis, Davis, CA USA 95616
| | - Keith Baar
- Department of Physiology and Membrane Biology, University of California Davis, Davis, CA USA 95616
| | - Steven G Kohama
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Portland, OR 97239, USA
| | - E Dale Abel
- Program in Molecular Medicine and Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Myung K Kim
- Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jay H Chung
- Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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31
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Escudero B, Herrero D, Torres Y, Cañón S, Molina A, Carmona RM, Suela J, Blanco L, Samper E, Bernad A. Polμ deficiency induces moderate shortening of P53 -/- mouse lifespan and modifies tumor spectrum. DNA Repair (Amst) 2017; 54:40-45. [PMID: 28460268 DOI: 10.1016/j.dnarep.2017.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 03/29/2017] [Accepted: 04/04/2017] [Indexed: 11/16/2022]
Abstract
Non-homologous end joining (NHEJ) is the main mechanism for double strand break (DSB) DNA repair. The error-prone DNA polymerase mu (Polμ) is involved in immunoglobulin variable region rearrangement and in general, NHEJ in non-lymphoid cells. Deletion of NHEJ factors in P53-/- mice, which are highly prone to development of T cell lymphoma, generally increases cancer incidence and shifts the tumor spectrum towards aggressive pro-B lymphoma. In contrast, Polμ deletion increased sarcoma incidence, proportionally reducing pro-B lymphoma development on the P53-deficient background. Array comparative genomic hybridization (aCGH) analyses showed DNA copy number alterations in both P53-/- and Polμ-/-P53-/- lymphomas. Our results also indicate that the increase in sarcoma incidence in Polμ-/-P53-/- mice could be associated with Cdk4 and Kub3 amplification and overexpression. These results identify a role for Polμ in the prevention of sarcomagenesis on a murine P53-deficient background, in contrast to most other NHEJ factors.
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Affiliation(s)
- Beatriz Escudero
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain; Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Diego Herrero
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain; Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Yaima Torres
- Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; NIMGenetics SL, 28049 Madrid, Spain
| | - Susana Cañón
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain; Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Antonio Molina
- Animal Unit, Fundación Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain
| | - Rosa M Carmona
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain; Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | | | - Luis Blanco
- Centro de Biología Molecular Severo Ochoa (CBMSO), 28049 Madrid, Spain
| | - Enrique Samper
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain; Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; NIMGenetics SL, 28049 Madrid, Spain
| | - Antonio Bernad
- Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain; Department of Regenerative Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
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Pan-Cancer Analysis of Genomic Sequencing Among the Elderly. Int J Radiat Oncol Biol Phys 2017; 98:726-732. [PMID: 28258894 DOI: 10.1016/j.ijrobp.2017.01.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 12/19/2016] [Accepted: 01/01/2017] [Indexed: 12/16/2022]
Abstract
PURPOSE We hypothesized that elderly patients might have age-specific genetic abnormalities yet be underrepresented in currently available sequencing repositories, which could limit the effect of sequencing efforts for this population. METHODS AND MATERIALS Leveraging The Cancer Genome Atlas (TCGA) data portal, 9 tumor types were analyzed. The frequency distribution of cancer by age was determined and compared with Surveillance, Epidemiology, and End Results data. Using the estimated median somatic mutational frequency of each tumor type, the samples needed beyond TCGA to detect a 10% mutational frequency were calculated. Microarray data from a separate prospective cohort were obtained from primary prostatectomy samples to determine whether elderly-specific transcriptomic alterations could be identified. RESULTS Of the 5236 TCGA samples, 73% were from patients aged <70 years. Comparing the distribution of TCGA samples by age to the Surveillance, Epidemiology, and End Results data, patients <70 years were well represented across most tumor types, but patients aged 80 to 99 years were underrepresented in all cancers (median TCGA underrepresentation of 167%). All cancers (except for colorectal) contained enough samples to detect a 10% mutational frequency in patients aged <60 years. In contrast, no cancer type had enough samples for which a 10% mutational frequency could be detected in patients aged ≥80 years. To further interrogate whether elderly patients with cancer were likely to harbor age-specific molecular abnormalities, we accessed transcriptomic data from a separate, larger database of >2000 prostate cancer samples. That analysis revealed significant differences in the expression of 10 genes in patients aged ≥70 years compared with those <70 years, of which 7 are involved in androgen signaling and/or DNA repair. CONCLUSIONS Elderly patients have been underrepresented in genomic sequencing studies. Our data suggest the presence of elderly-specific molecular alterations. Further dedicated efforts to understand the biology of cancer among the elderly will be important moving forward.
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Abstract
DNA double-strand breaks (DSBs) are rare, but highly toxic, lesions requiring orchestrated and conserved machinery to prevent adverse consequences, such as cell death and cancer-causing genome structural mutations. DSBs trigger the DNA damage response (DDR) that directs a cell to repair the break, undergo apoptosis, or become senescent. There is increasing evidence that the various endpoints of DSB processing by different cells and tissues are part of the aging phenotype, with each stage of the DDR associated with specific aging pathologies. In this Perspective, we discuss the possibility that DSBs are major drivers of intrinsic aging, highlighting the dynamics of spontaneous DSBs in relation to aging, the distinct age-related pathologies induced by DSBs, and the segmental progeroid phenotypes in humans and mice with genetic defects in DSB repair. A model is presented as to how DSBs could drive some of the basic mechanisms underlying age-related functional decline and death.
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Affiliation(s)
- Ryan R White
- Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave., Bronx, NY 10461, USA.
| | - Jan Vijg
- Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave., Bronx, NY 10461, USA.
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Mishra S, Kumar R, Malhotra N, Singh N, Dada R. Mild oxidative stress is beneficial for sperm telomere length maintenance. World J Methodol 2016; 6:163-170. [PMID: 27376021 PMCID: PMC4921947 DOI: 10.5662/wjm.v6.i2.163] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 11/24/2015] [Accepted: 03/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate telomere length in sperm DNA and its correlation with oxidative stress (normal, mild, severe).
METHODS: The study included infertile men (n = 112) and age matched fertile controls (n = 102). The average telomere length from the sperm DNA was measured using a quantitative real time PCR based assay. Seminal reactive oxygen species (ROS) and 8-Isoprostane (8-IP) levels were measured by chemiluminescence assay and ELISA respectively.
RESULTS: Average sperm telomere length in infertile men and controls was 0.609 ± 0.15 and 0.789 ± 0.060, respectively (P < 0.0001). Seminal ROS levels in infertile was higher [66.61 ± 28.32 relative light units (RLU)/s/million sperm] than in controls (14.04 ± 10.67 RLU/s/million sperm) (P < 0.0001). The 8-IP level in infertile men was significantly higher (421.55 ± 131.29 pg/mL) than in controls (275.94 ± 48.13 pg/mL) (P < 0.001). When correlated to oxidative stress, in normal range of oxidative stress (ROS, 0-21.3 RLU/s/million sperm) the average telomere length in cases was 0.663 ± 0.14, in mild oxidative stress (ROS, 21.3-35 RLU/s/million sperm) it was elevated (0.684 ± 0.12) and in severe oxidative stress (ROS > 35 RLU/s/million sperm) average telomere length was decreased to 0.595 ± 0.15.
CONCLUSION: Mild oxidative stress results in lengthening of telomere length, but severe oxidative stress results in shorter telomeres. Although telomere maintenance is a complex trait, the study shows that mild oxidative stress is beneficial in telomere length maintenance and thus a delicate balance needs to be established to maximize the beneficial effects of free radicals and prevent harmful effects of supra physiological levels. Detailed molecular evaluation of telomere structure, its correlation with oxidative stress would aid in elucidating the cause of accelerated telomere length attrition.
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35
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Gorbunova V, Seluanov A. DNA double strand break repair, aging and the chromatin connection. Mutat Res 2016; 788:2-6. [PMID: 26923716 DOI: 10.1016/j.mrfmmm.2016.02.004] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Revised: 02/01/2016] [Accepted: 02/10/2016] [Indexed: 01/07/2023]
Abstract
Are DNA damage and mutations possible causes or consequences of aging? This question has been hotly debated by biogerontologists for decades. The importance of DNA damage as a possible driver of the aging process went from being widely recognized to then forgotten, and is now slowly making a comeback. DNA double strand breaks (DSBs) are particularly relevant to aging because of their toxicity, increased frequency with age and the association of defects in their repair with premature aging. Recent studies expand the potential impact of DNA damage and mutations on aging by linking DNA DSB repair and age-related chromatin changes. There is overwhelming evidence that increased DNA damage and mutations accelerate aging. However, an ultimate proof of causality would be to show that enhanced genome and epigenome stability delays aging. This is not an easy task, as improving such complex biological processes is infinitely more difficult than disabling it. We will discuss the possibility that animal models with enhanced DNA repair and epigenome maintenance will be generated in the near future.
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Affiliation(s)
- Vera Gorbunova
- University of Rochester, Department of Biology, Hutchison Hall, RC, Rochester, NY 14627, USA.
| | - Andrei Seluanov
- University of Rochester, Department of Biology, Hutchison Hall, RC, Rochester, NY 14627, USA
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36
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Swahari V, Nakamura A. Speeding up the clock: The past, present and future of progeria. Dev Growth Differ 2015; 58:116-30. [DOI: 10.1111/dgd.12251] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 10/15/2015] [Accepted: 10/15/2015] [Indexed: 12/18/2022]
Affiliation(s)
- Vijay Swahari
- Neuroscience Center; University of North Carolina; Chapel Hill North Carolina USA
| | - Ayumi Nakamura
- Neuroscience Center; University of North Carolina; Chapel Hill North Carolina USA
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37
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Spontaneous tumor development in bone marrow-rescued DNA-PKcs(3A/3A) mice due to dysfunction of telomere leading strand deprotection. Oncogene 2015; 35:3909-18. [PMID: 26616856 PMCID: PMC4885801 DOI: 10.1038/onc.2015.459] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 10/29/2015] [Accepted: 10/30/2015] [Indexed: 12/16/2022]
Abstract
Phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at the Thr2609 cluster is essential for its complete function in DNA repair and tissue stem cell homeostasis. This phenomenon is demonstrated by congenital bone marrow failure occurring in DNA-PKcs3A/3A mutant mice, which require bone marrow transplantation (BMT) to prevent early mortality. Surprisingly, an increased incidence of spontaneous tumors, especially skin cancer, was observed in adult BMT-rescued DNA-PKcs3A/3A mice. Upon further investigation we found that spontaneous γH2AX foci occurred in DNA-PKcs3A/3A skin biopsies and primary keratinocytes and that these foci overlapped with telomeres during mitosis, indicating impairment of telomere replication and maturation. Consistently, we observed significantly elevated frequencies of telomere fusion events in DNA-PKcs3A/3A cells as compared to wild type and DNA-PKcs knockout cells. In addition, a previously identified DNA-PKcs Thr2609Pro mutation, found in breast cancer, also induces a similar impairment of telomere leading end maturation. Taken together, our current analyses indicate that the functional DNA-PKcs T2609 cluster is required to facilitate telomere leading strand maturation and prevention of genomic instability and cancer development.
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Mateos-Aierdi AJ, Goicoechea M, Aiastui A, Fernández-Torrón R, Garcia-Puga M, Matheu A, López de Munain A. Muscle wasting in myotonic dystrophies: a model of premature aging. Front Aging Neurosci 2015. [PMID: 26217220 PMCID: PMC4496580 DOI: 10.3389/fnagi.2015.00125] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Myotonic dystrophy type 1 (DM1 or Steinert’s disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3′ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9(CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.
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Affiliation(s)
- Alba Judith Mateos-Aierdi
- Neuroscience Area, Biodonostia Health Research Institute San Sebastián, Spain ; CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain
| | - Maria Goicoechea
- Neuroscience Area, Biodonostia Health Research Institute San Sebastián, Spain ; CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain
| | - Ana Aiastui
- CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain ; Cell Culture Platform, Biodonostia Health Research Institute, San Sebastián Spain
| | - Roberto Fernández-Torrón
- Neuroscience Area, Biodonostia Health Research Institute San Sebastián, Spain ; CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain ; Department of Neurology, Hospital Universitario Donostia, San Sebastián Spain
| | - Mikel Garcia-Puga
- Oncology Area, Biodonostia Health Research Institute San Sebastián, Spain
| | - Ander Matheu
- Oncology Area, Biodonostia Health Research Institute San Sebastián, Spain
| | - Adolfo López de Munain
- Neuroscience Area, Biodonostia Health Research Institute San Sebastián, Spain ; CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain ; Department of Neurology, Hospital Universitario Donostia, San Sebastián Spain ; Department of Neuroscience, Universidad del País Vasco UPV-EHU San Sebastián, Spain
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Czarny P, Pawlowska E, Bialkowska-Warzecha J, Kaarniranta K, Blasiak J. Autophagy in DNA damage response. Int J Mol Sci 2015; 16:2641-62. [PMID: 25625517 PMCID: PMC4346856 DOI: 10.3390/ijms16022641] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 01/12/2015] [Indexed: 12/15/2022] Open
Abstract
DNA damage response (DDR) involves DNA repair, cell cycle regulation and apoptosis, but autophagy is also suggested to play a role in DDR. Autophagy can be activated in response to DNA-damaging agents, but the exact mechanism underlying this activation is not fully understood, although it is suggested that it involves the inhibition of mammalian target of rapamycin complex 1 (mTORC1). mTORC1 represses autophagy via phosphorylation of the ULK1/2-Atg13-FIP200 complex thus preventing maturation of pre-autophagosomal structures. When DNA damage occurs, it is recognized by some proteins or their complexes, such as poly(ADP)ribose polymerase 1 (PARP-1), Mre11-Rad50-Nbs1 (MRN) complex or FOXO3, which activate repressors of mTORC1. SQSTM1/p62 is one of the proteins whose levels are regulated via autophagic degradation. Inhibition of autophagy by knockout of FIP200 results in upregulation of SQSTM1/p62, enhanced DNA damage and less efficient damage repair. Mitophagy, one form of autophagy involved in the selective degradation of mitochondria, may also play role in DDR. It degrades abnormal mitochondria and can either repress or activate apoptosis, but the exact mechanism remains unknown. There is a need to clarify the role of autophagy in DDR, as this process may possess several important biomedical applications, involving also cancer therapy.
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Affiliation(s)
- Piotr Czarny
- Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
| | - Elzbieta Pawlowska
- Department of Orthodontics, Medical University of Lodz, Pomorska 251, 92-216 Lodz, Poland.
| | - Jolanta Bialkowska-Warzecha
- Department of Infectious and Liver Diseases, Medical University of Lodz, Kniaziewicza 1/5, 92-347 Lodz, Poland.
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio FI-70211, Finland.
| | - Janusz Blasiak
- Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
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Leandro GS, Sykora P, Bohr VA. The impact of base excision DNA repair in age-related neurodegenerative diseases. Mutat Res 2015; 776:31-9. [PMID: 26255938 PMCID: PMC5576886 DOI: 10.1016/j.mrfmmm.2014.12.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 12/23/2014] [Accepted: 12/26/2014] [Indexed: 12/29/2022]
Abstract
The aging process and several age-related neurodegenerative disorders have been linked to elevated levels of DNA damage induced by ROS and deficiency in DNA repair mechanisms. DNA damage induced by ROS is a byproduct of cellular respiration and accumulation of damage over time, is a fundamental aspect of a main theory of aging. Mitochondria have a pivotal role in generating cellular oxidative stress, and mitochondrial dysfunction has been associated with several diseases. DNA base excision repair is considered the major pathway for repair of oxidized bases in DNA both in the nuclei and in mitochondria, and in neurons this mechanism is particularly important because non-diving cells have limited back-up DNA repair mechanisms. An association between elevated oxidative stress and a decrease in BER is strongly related to the aging process and has special relevance in age-related neurodegenerative diseases. Here, we review the role of DNA repair in aging, focusing on the implications of the DNA base excision repair pathways and how alterations in expression of these DNA repair proteins are related to the aging process and to age-related neurodegenerative diseases.
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Affiliation(s)
- Giovana S Leandro
- Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, 251 Bayview Blvd., Baltimore, MD 21224, United States; Department of Genetics, Ribeirao Preto Medical School, University of Sao Paulo, Avenida Bandeirantes, 3900, Ribeirao Preto, SP 14049-900, Brazil
| | - Peter Sykora
- Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, 251 Bayview Blvd., Baltimore, MD 21224, United States.
| | - Vilhelm A Bohr
- Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, 251 Bayview Blvd., Baltimore, MD 21224, United States.
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The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency. PLoS One 2014; 9:e93568. [PMID: 24740260 PMCID: PMC3989187 DOI: 10.1371/journal.pone.0093568] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 03/05/2014] [Indexed: 01/01/2023] Open
Abstract
Ku80 and DNA-PKCS are both involved in the repair of double strand DNA breaks via the nonhomologous end joining (NHEJ) pathway. While ku80-/- mice exhibit a severely reduced lifespan and size, this phenotype is less pronounced in dna-pkcs-/- mice. However, these observations are based on independent studies with varying genetic backgrounds. Here, we generated ku80-/-, dna-pkcs-/- and double knock out mice in a C57Bl6/J*FVB F1 hybrid background and compared their lifespan, end of life pathology and mutation frequency in liver and spleen using a lacZ reporter. Our data confirm that inactivation of Ku80 and DNA-PKCS causes reduced lifespan and bodyweights, which is most severe in ku80-/- mice. All mutant mice exhibited a strong increase in lymphoma incidence as well as other aging-related pathology (skin epidermal and adnexal atrophy, trabacular bone reduction, kidney tubular anisokaryosis, and cortical and medullar atrophy) and severe lymphoid depletion. LacZ mutation frequency analysis did not show strong differences in mutation frequencies between knock out and wild type mice. The ku80-/- mice had the most severe phenotype and the Ku80-mutation was dominant over the DNA-PKCS-mutation. Presumably, the more severe degenerative effect of Ku80 inactivation on lifespan compared to DNA-PKCS inactivation is caused by additional functions of Ku80 or activity of free Ku70 since both Ku80 and DNA-PKCS are essential for NHEJ.
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Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair. PLoS One 2014; 9:e86358. [PMID: 24466051 PMCID: PMC3900520 DOI: 10.1371/journal.pone.0086358] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 12/07/2013] [Indexed: 01/25/2023] Open
Abstract
Ku70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA dependent-protein kinase catalytic subunit (DNA-PKCS) to repair DNA double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. As expected mutating these genes in mice caused a similar DSB repair-defective phenotype. However, ku70-/- cells and ku80-/- cells also appeared to have a defect in base excision repair (BER). BER corrects base lesions, apurinic/apyrimidinic (AP) sites and single stand breaks (SSBs) utilizing a variety of proteins including glycosylases, AP endonuclease 1 (APE1) and DNA Polymerase β (Pol β). In addition, deleting Ku70 was not equivalent to deleting Ku80 in cells and mice. Therefore, we hypothesized that free Ku70 (not bound to Ku80) and/or free Ku80 (not bound to Ku70) possessed activity that influenced BER. To further test this hypothesis we performed two general sets of experiments. The first set showed that deleting either Ku70 or Ku80 caused an NHEJ-independent defect. We found ku80-/- mice had a shorter life span than dna-pkcs-/- mice demonstrating a phenotype that was greater than deleting the holoenzyme. We also found Ku70-deletion induced a p53 response that reduced the level of small mutations in the brain suggesting defective BER. We further confirmed that Ku80-deletion impaired BER via a mechanism that was not epistatic to Pol β. The second set of experiments showed that free Ku70 and free Ku80 could influence BER. We observed that deletion of either Ku70 or Ku80, but not both, increased sensitivity of cells to CRT0044876 (CRT), an agent that interferes with APE1. In addition, free Ku70 and free Ku80 bound to AP sites and in the case of Ku70 inhibited APE1 activity. These observations support a novel role for free Ku70 and free Ku80 in altering BER.
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Fu L, Kettner NM. The circadian clock in cancer development and therapy. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2013; 119:221-82. [PMID: 23899600 PMCID: PMC4103166 DOI: 10.1016/b978-0-12-396971-2.00009-9] [Citation(s) in RCA: 175] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Most aspects of mammalian function display circadian rhythms driven by an endogenous clock. The circadian clock is operated by genes and comprises a central clock in the brain that responds to environmental cues and controls subordinate clocks in peripheral tissues via circadian output pathways. The central and peripheral clocks coordinately generate rhythmic gene expression in a tissue-specific manner in vivo to couple diverse physiological and behavioral processes to periodic changes in the environment. However, with the industrialization of the world, activities that disrupt endogenous homeostasis with external circadian cues have increased. This change in lifestyle has been linked to an increased risk of diseases in all aspects of human health, including cancer. Studies in humans and animal models have revealed that cancer development in vivo is closely associated with the loss of circadian homeostasis in energy balance, immune function, and aging, which are supported by cellular functions important for tumor suppression including cell proliferation, senescence, metabolism, and DNA damage response. The clock controls these cellular functions both locally in cells of peripheral tissues and at the organismal level via extracellular signaling. Thus, the hierarchical mammalian circadian clock provides a unique system to study carcinogenesis as a deregulated physiological process in vivo. The asynchrony between host and malignant tissues in cell proliferation and metabolism also provides new and exciting options for novel anticancer therapies.
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Affiliation(s)
- Loning Fu
- Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Nicole M. Kettner
- Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
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Li Y, Zhao D. Basics of Molecular Biology. ADVANCED TOPICS IN SCIENCE AND TECHNOLOGY IN CHINA 2013. [PMCID: PMC7122053 DOI: 10.1007/978-3-642-34303-2_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Molecular biology is the study of biology on molecular level. The field overlaps with areas of biology and chemistry, particularly genetics and biochemistry. Molecular biology chiefly concerns itself with understanding the interactions between the various systems of a cell, including the interactions between DNA (deoxyribonucleic acid), RNA (Ribonucleic acid) and protein biosynthesis as well as learning how these interactions are regulated[1].
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Nowsheen S, Yang E. The intersection between DNA damage response and cell death pathways. Exp Oncol 2012; 34:243-254. [PMID: 23070009 PMCID: PMC3754840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Apoptosis is a finely regulated process that serves to determine the fate of cells in response to various stresses. One such stress is DNA damage, which not only can signal repair processes but is also intimately involved in regulating cell fate. In this review we examine the relationship between the DNA damage/repair response in cell survival and apoptosis following insults to the DNA. Elucidating these pathways and the crosstalk between them is of great importance, as they eventually contribute to the etiology of human disease such as cancer and may play key roles in determining therapeutic response. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".
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Affiliation(s)
- S. Nowsheen
- Departments of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Alabama, USA
| | - E.S. Yang
- Departments of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Alabama, USA
- Departments of Cell, Developmental, and Integrative Biology, Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Alabama, USA
- Departments of Pharmacology and Toxicology, Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Alabama, USA
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PARP1 and DNA-PKcs synergize to suppress p53 mutation and telomere fusions during T-lineage lymphomagenesis. Oncogene 2012; 32:1761-71. [PMID: 22614020 DOI: 10.1038/onc.2012.199] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Poly(ADP-ribose) polymerase 1 (PARP1) interacts genetically with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress early-onset T-lineage lymphomas in the mouse, but the underlying mechanisms have remained unknown. To address this question, we analyzed a series of lymphomas arising in PARP1(-/-)/DNA-PKcs(-/-) (P1(-/-)/D(-/-)) mice. We found that, despite defective V(D)J recombination, P1(-/-)/D(-/-) lymphomas lacked clonal reciprocal translocations involving antigen-receptor loci. Instead, tumor cells were characterized by aneuploidy driven by two main mechanisms: p53 inactivation and abnormal chromosome disjunction due to telomere fusions (TFs). Aberrant accumulation of p53 was observed in 13/19 (68.4%) lymphomas. Sequence analysis revealed five p53 mutations: three missense point mutations (one transition in exon 8 and two transversions in exons 5 and 8, respectively), one in-frame 5-11 microindel in exon 7 and a 410-bp deletion encompassing exons 5-8, resulting in a truncated protein. Analysis of tumor metaphases using sequential telomere fluorescent in-situ hybridization and spectral karyotyping revealed that nine out of nine lymphomas contained TFs. Mutant but not wild-type p53 status was associated with frequent clonal and nonclonal TFs, suggesting that p53 normally limits the extent of telomere dysfunction during transformation. Chromosomes involved in TFs were more likely to be aneuploid than chromosomes not involved in TFs in the same metaphases, regardless of the p53 status, indicating that TFs promote aneuploidy via a mechanism that is distinct from p53 loss. Finally, analysis of radiation responses in P1(-/-)/D(-/-), and control primary cells and tissues indicates that loss of PARP1 increases in vivo radiosensitivity and genomic instability in DNA-PKcs-deficient mice without impairing p53 stabilization and effector functions, suggesting a more severe defect in double-strand break (DSB) repair in double mutants. Together, our findings uncover defective DSB repair leading to tumor suppressor inactivation and abnormal segregation of fused chromosomes as two novel mechanisms promoting tumorigenesis in thymocytes lacking PARP1 and DNA-PKcs.
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Min X, Tang J, Wang Y, Yu M, Zhao L, Yang H, Zhang P, Ma Y. PI3K-like kinases restrain Pim gene expression in endothelial cells. ACTA ACUST UNITED AC 2012; 32:17-23. [PMID: 22282239 DOI: 10.1007/s11596-012-0003-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2010] [Indexed: 01/28/2023]
Abstract
Pim kinases contribute to tumor formation and development of lymphoma, which shows enhanced DNA replication, DNA recombination and repair. Endothelial cells^(ECs) express all the three members of Pim kinase gene family. We hypothesized that DNA repair gene would regulate Pim expression in ECs. Human umbilical vein endothelial cells (HUVECs) were isolated and maintained in M199 culture medium. The cellular distribution of Pim-3 in ECs was determined by immunofluorescent staining. The siRNA fragments were synthesized and transfected by using Lipofectamine LTX. The total cellular RNA was extracted from the cells by using Trizol reagent. cDNAs were quantified by semi-quantity PCR. The effects of LY294002 and wortmannin on RNA stability in ECs were also examined. Our data showed that LY294002 and wortmannin, phosphatidylinositol 3-kinase (PI3K) and PI3K-like kinase inhibitors, increased Pim mRNA expression in ECs without altering the mRNA stability. RNA interference (RNAi) targeting DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia telangiectasia mutated (ATM) increased mRNA expression of Pim-3 and Pim-1, respectively. Silencing of Akt decreased Pim-1 instead of Pm-2 and Pim-3 gene expression in ECs. But etoposide, a nucleoside analogue, which could activate DNA-PKcs and ATM, increased Pim expression in ECs. Our study indicates that the expression of Pim kinases is physiologically related to DNA-PKcs and ATM in ECs.
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Affiliation(s)
- Xinwen Min
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Institute of Cardiovascular Science, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, China
| | - Jie Tang
- Department of Anatomy, Hubei University of Medicine, Shiyan, 442000, China
| | - Yinfang Wang
- Department of Physiology, Hubei University of Medicine, Shiyan, 442000, China
| | - Minghua Yu
- Department of Anatomy, Hubei University of Medicine, Shiyan, 442000, China
| | - Libing Zhao
- Institute of Cardiovascular Science, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, China
| | - Handong Yang
- Institute of Cardiovascular Science, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, China
| | - Peng Zhang
- Institute of Cardiovascular Science, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, China
| | - Yexin Ma
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Lee JE, Heo JI, Park SH, Kim JH, Kho YJ, Kang HJ, Chung HY, Yoon JL, Lee JY. Calorie restriction (CR) reduces age-dependent decline of non-homologous end joining (NHEJ) activity in rat tissues. Exp Gerontol 2011; 46:891-6. [PMID: 21821112 DOI: 10.1016/j.exger.2011.07.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2010] [Revised: 06/27/2011] [Accepted: 07/20/2011] [Indexed: 11/17/2022]
Abstract
Even though CR has shown to enhance base excision repair (BER) and nucleotide excision repair (NER) capacities, it has not been reported whether CR can enhance non-homologous end joining (NHEJ) activity. To examine the effect of CR on NHEJ activity, ad libitum (AL)- and calorie restricted (CR)-dieted rats were used. Age-dependent decline of NHEJ activity was apparent in the lung, liver, and kidney and appeared to be slightly decreased in spleen. CR reduced age-dependent decline of NHEJ activity in all tissues, even though the extent of recovery was variable among tissues. Moreover, CR appeared to reduce age-dependent decline of XRCC4 protein level. These results suggest that CR could reduce age-dependent decline of NHEJ activity in various tissues of rats possibly through up-regulation of XRCC4.
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Affiliation(s)
- Jae-Eun Lee
- Department of Family Medicine, Hangang Secred Heart Hospital, Hallym University Medical Center, Seoul, South Korea
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Lee YF, Liu S, Liu NC, Wang RS, Chen LM, Lin WJ, Ting HJ, Ho HC, Li G, Puzas EJ, Wu Q, Chang C. Premature aging with impaired oxidative stress defense in mice lacking TR4. Am J Physiol Endocrinol Metab 2011; 301:E91-8. [PMID: 21521714 PMCID: PMC3129845 DOI: 10.1152/ajpendo.00701.2010] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Early studies suggest that TR4 nuclear receptor is a key transcriptional factor regulating various biological activities, including reproduction, cerebella development, and metabolism. Here we report that mice lacking TR4 (TR4(-/-)) exhibited increasing genome instability and defective oxidative stress defense, which are associated with premature aging phenotypes. At the cellular level, we observed rapid cellular growth arrest and less resistance to oxidative stress and DNA damage in TR4(-/-) mouse embryonic fibroblasts (MEFs) in vitro. Restoring TR4 or supplying the antioxidant N-acetyl-l-cysteine (NAC) to TR4(-/-) MEFs reduced the DNA damage and slowed down cellular growth arrest. Focused qPCR array revealed alteration of gene profiles in the DNA damage response (DDR) and anti-reactive oxygen species (ROS) pathways in TR4(-/-) MEFs, which further supports the hypothesis that the premature aging in TR4(-/-) mice might stem from oxidative DNA damage caused by increased oxidative stress or compromised genome integrity. Together, our finding identifies a novel role of TR4 in mediating the interplay between oxidative stress defense and aging.
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Affiliation(s)
- Yi-Fen Lee
- George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Orthopaedics, University of Rochester Medical Center, Rochester, New York 14620, USA.
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Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum. Oncogene 2011; 30:4740-9. [PMID: 21602895 DOI: 10.1038/onc.2011.178] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Heterozygous Patched1 (Ptc1(+/-)) mice are prone to medulloblastoma (MB), and exposure of newborn mice to ionizing radiation dramatically increases the frequency and shortens the latency of MB. In Ptc1(+/-) mice, MB is characterized by loss of the normal remaining Ptc1 allele, suggesting that genome rearrangements may be key events in MB development. Recent evidence indicates that brain tumors may be linked to defects in DNA-damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints, apoptosis and DNA repair result in MB in mice. Non-homologous end joining (NHEJ) and homologous recombination (HR) contribute to genome stability, and deficiencies in either pathway predispose to genome rearrangements. To test the role of defective HR or NHEJ in tumorigenesis, control and irradiated Ptc1(+/-) mice with two, one or no functional Rad54 or DNA-protein kinase catalytic subunit (DNA-PKcs) alleles were monitored for MB development. We also examined the effect of Rad54 or DNA-PKcs deletion on the processing of endogenous and radiation-induced double-strand breaks (DSBs) in neural precursors of the developing cerebellum, the cells of origin of MB. We found that, although HR and NHEJ collaborate in protecting cells from DNA damage and apoptosis, they have opposite roles in MB tumorigenesis. In fact, although Rad54 deficiency increased both spontaneous and radiation-induced MB development, DNA-PKcs disruption suppressed MB tumorigenesis. Together, our data provide the first evidence that Rad54-mediated HR in vivo is important for suppressing tumorigenesis by maintaining genomic stability.
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