|
1
|
Martinez-Fernandez V, Barascu A, Teixeira MT. Life and Death without Telomerase: The Saccharomyces cerevisiae Model. Cold Spring Harb Perspect Biol 2025; 17:a041699. [PMID: 39694811 PMCID: PMC12047662 DOI: 10.1101/cshperspect.a041699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Abstract
Saccharomyces cerevisiae, a model organism in telomere biology, has been instrumental in pioneering a comprehensive understanding of the molecular processes that occur in the absence of telomerase across eukaryotes. This exploration spans investigations into telomere dynamics, intracellular signaling cascades, and organelle-mediated responses, elucidating their impact on proliferative capacity, genome stability, and cellular variability. Through the lens of budding yeast, numerous sources of cellular heterogeneity have been identified, dissected, and modeled, shedding light on the risks associated with telomeric state transitions, including the evasion of senescence. Moreover, the unraveling of the intricate interplay between the nucleus and other organelles upon telomerase inactivation has provided insights into eukaryotic evolution and cellular communication networks. These contributions, akin to milestones achieved using budding yeast, such as the discovery of the cell cycle, DNA damage checkpoint mechanisms, and DNA replication and repair processes, have been of paramount significance for the telomere field. Particularly, these insights extend to understanding replicative senescence as an anticancer mechanism in humans and enhancing our understanding of eukaryotes' evolution.
Collapse
Affiliation(s)
- Veronica Martinez-Fernandez
- Sorbonne Université, CNRS, Institut de Biologie Physico-Chimique, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, LBMCE, F-75005 Paris, France
| | - Aurélia Barascu
- Sorbonne Université, CNRS, Institut de Biologie Physico-Chimique, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, LBMCE, F-75005 Paris, France
| | - Maria Teresa Teixeira
- Sorbonne Université, CNRS, Institut de Biologie Physico-Chimique, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, LBMCE, F-75005 Paris, France
| |
Collapse
|
|
2
|
Rat A, Martinez Fernandez V, Doumic M, Teixeira MT, Xu Z. Mathematical model linking telomeres to senescence in Saccharomyces cerevisiae reveals cell lineage versus population dynamics. Nat Commun 2025; 16:1024. [PMID: 39863614 PMCID: PMC11762778 DOI: 10.1038/s41467-025-56196-z] [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: 01/03/2024] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Telomere shortening ultimately causes replicative senescence. However, identifying the mechanisms driving replicative senescence in cell populations is challenging due to the heterogeneity of telomere lengths and the asynchrony of senescence onset. Here, we present a mathematical model of telomere shortening and replicative senescence in Saccharomyces cerevisiae which is quantitatively calibrated and validated using data of telomerase-deficient single cells. Simulations of yeast populations, where cells with varying proliferation capacities compete against each other, show that the distribution of telomere lengths of the initial population shapes population growth, especially through the distribution of cells' shortest telomere lengths. We also quantified how factors influencing cell viability independently of telomeres can impact senescence rates. Overall, we demonstrate a temporal evolution in the composition of senescent cell populations-from a state directly linked to critically short telomeres to a state where senescence onset becomes stochastic. This population structure may promote genome instability and facilitate senescence escape.
Collapse
Affiliation(s)
- Anaïs Rat
- Aix Marseille Univ, CNRS, I2M, Centrale Marseille, Marseille, France
- Sorbonne Université, CNRS, Université de Paris, Inria, Laboratoire Jacques-Louis Lions UMR7598, Paris, France
- Univ Brest, CNRS UMR 6205, Laboratoire de Mathématiques de Bretagne Atlantique, Brest, France
| | - Veronica Martinez Fernandez
- Sorbonne Université, CNRS, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, LBMCE, Paris, France
| | - Marie Doumic
- Sorbonne Université, CNRS, Université de Paris, Inria, Laboratoire Jacques-Louis Lions UMR7598, Paris, France.
- CMAP, Inria, IP Paris, Ecole polytechnique, CNRS, Palaiseau, France.
| | - Maria Teresa Teixeira
- Sorbonne Université, CNRS, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, LBMCE, Paris, France.
| | - Zhou Xu
- Sorbonne Université, CNRS, Laboratory of Computational and Quantitative Biology, LCQB, Paris, France
| |
Collapse
|
|
3
|
Barchitta M, Maugeri A, La Mastra C, Favara G, La Rosa MC, Magnano San Lio R, Gholizade Atani Y, Gallo G, Agodi A. Pre-pregnancy BMI, gestational weight gain, and telomere length in amniotic fluid: a causal graph analysis. Sci Rep 2024; 14:23396. [PMID: 39379607 PMCID: PMC11461511 DOI: 10.1038/s41598-024-74765-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 09/30/2024] [Indexed: 10/10/2024] Open
Abstract
Previous investigations have suggested a potential association between pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with telomere length (TL) in various tissues of pregnant women and newborns. Nonetheless, as association does not imply causation, our objective was to investigate the causal connections among pre-pregnancy BMI, GWG, and TL in amniotic fluid. The analysis included 136 mother-child pairs from the Mamma & Bambino cohort, and three causal graph models were developed to depict the interconnections between pre-pregnancy BMI, GWG, and TL. Causal graph analysis was conducted utilizing the do-operator to estimate the causal effect of GWG and the controlled direct effect of pregestational BMI. We revealed that transitioning from non-adequate to adequate GWG had a positive impact on the probability of having "long" TL (i.e., a value greater than the population median) in all three models. When considering the effect of pre-pregnancy BMI, the highest probability of "long" TL was observed in normal weight women with adequate GWG. In contrast, the effect of adequate GWG became minimal among overweight women. These results shed light on the potential causality between pre-pregnancy BMI, GWG, and TL in amniotic fluid, emphasizing the importance of appropriate weight management before and during pregnancy for optimal TL outcomes.
Collapse
Affiliation(s)
- M Barchitta
- Department of Medical and Surgical Sciences and Advanced Technologies 'GF Ingrassia', University of Catania, Catania, Italy
| | - A Maugeri
- Department of Medical and Surgical Sciences and Advanced Technologies 'GF Ingrassia', University of Catania, Catania, Italy
| | - C La Mastra
- Department of Medical and Surgical Sciences and Advanced Technologies 'GF Ingrassia', University of Catania, Catania, Italy
| | - G Favara
- Department of Medical and Surgical Sciences and Advanced Technologies 'GF Ingrassia', University of Catania, Catania, Italy
| | - M C La Rosa
- Department of Medical and Surgical Sciences and Advanced Technologies 'GF Ingrassia', University of Catania, Catania, Italy
| | - R Magnano San Lio
- Department of Medical and Surgical Sciences and Advanced Technologies 'GF Ingrassia', University of Catania, Catania, Italy
| | - Y Gholizade Atani
- Department of Mathematics and Informatics, University of Catania, Catania, Italy
| | - G Gallo
- Department of Mathematics and Informatics, University of Catania, Catania, Italy
| | - A Agodi
- Department of Medical and Surgical Sciences and Advanced Technologies 'GF Ingrassia', University of Catania, Catania, Italy.
| |
Collapse
|
|
4
|
Bian Y, Lv F, Pan H, Ren W, Zhang W, Wang Y, Cao Y, Li W, Wang W. Fusion Dynamics and Size-Dependence of Droplet Microstructure in ssDNA-Mediated Protein Phase Separation. JACS AU 2024; 4:3690-3704. [PMID: 39328748 PMCID: PMC11423313 DOI: 10.1021/jacsau.4c00690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 08/27/2024] [Accepted: 08/27/2024] [Indexed: 09/28/2024]
Abstract
Biomolecular condensation involving proteins and nucleic acids has been recognized to play crucial roles in genome organization and transcriptional regulation. However, the biophysical mechanisms underlying the droplet fusion dynamics and microstructure evolution during the early stage of liquid-liquid phase separation (LLPS) remain elusive. In this work, we study the phase separation of linker histone H1, which is among the most abundant chromatin proteins, in the presence of single-stranded DNA (ssDNA) capable of forming a G-quadruplex by using molecular simulations and experimental characterization. We found that droplet fusion is a rather stochastic and kinetically controlled process. Productive fusion events are triggered by the formation of ssDNA-mediated electrostatic bridges within the droplet contacting zone. The droplet microstructure is size-dependent and evolves driven by maximizing the number of electrostatic contacts. We also showed that the folding of ssDNA to the G-quadruplex promotes LLPS by increasing the multivalency and strength of protein-DNA interactions. These findings provide deep mechanistic insights into the growth dynamics of biomolecular droplets and highlight the key role of kinetic control during the early stage of ssDNA-protein condensation.
Collapse
Affiliation(s)
- Yunqiang Bian
- Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang, China
| | - Fangyi Lv
- Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang, China
- Department of Physics, Wenzhou University, Wenzhou 325035, China
| | - Hai Pan
- Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang, China
| | - Weitong Ren
- Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang, China
| | - Weiwei Zhang
- Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang, China
| | - Yanwei Wang
- Department of Physics, Wenzhou University, Wenzhou 325035, China
| | - Yi Cao
- Department of Physics, National Laboratory of Solid State Microstructure, Nanjing University, Nanjing 210093, China
- Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang, China
| | - Wenfei Li
- Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang, China
- Department of Physics, National Laboratory of Solid State Microstructure, Nanjing University, Nanjing 210093, China
| | - Wei Wang
- Department of Physics, National Laboratory of Solid State Microstructure, Nanjing University, Nanjing 210093, China
| |
Collapse
|
|
5
|
Kang K, Lin X, Chen P, Liu H, Liu F, Xiong W, Li G, Yi M, Li X, Wang H, Xiang B. T cell exhaustion in human cancers. Biochim Biophys Acta Rev Cancer 2024; 1879:189162. [PMID: 39089484 DOI: 10.1016/j.bbcan.2024.189162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024]
Abstract
T cell exhaustion refers to a progressive state in which T cells become functionally impaired due to sustained antigenic stimulation, which is characterized by increased expression of immune inhibitory receptors, but weakened effector functions, reduced self-renewal capacity, altered epigenetics, transcriptional programme and metabolism. T cell exhaustion is one of the major causes leading to immune escape of cancer, creating an environment that supports tumor development and metastatic spread. In addition, T cell exhaustion plays a pivotal role to the efficacy of current immunotherapies for cancer. This review aims to provide a comprehensive view of roles of T cell exhaustion in cancer development and progression. We summerized the regulatory mechanisms that involved in T cell exhaustion, including transcription factors, epigenetic and metabolic reprogramming events, and various microenvironmental factors such as cytokines, microorganisms, and tumor autocrine substances. The paper also discussed the challenges posed by T cell exhaustion to cancer immunotherapies, including immune checkpoint blockade (ICB) therapies and chimeric antigen receptor T cell (CAR-T) therapy, highlightsing the obstacles encountered in ICB therapies and CAR-T therapies due to T cell exhaustion. Finally, the article provides an overview of current therapeutic options aimed to reversing or alleviating T cell exhaustion in ICB and CAR-T therapies. These therapeutic approaches seek to overcome T cell exhaustion and enhance the effectiveness of immunotherapies in treating tumors.
Collapse
Affiliation(s)
- Kuan Kang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Xin Lin
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Pan Chen
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China
| | - Huai Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Feng Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Wei Xiong
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Guiyuan Li
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Mei Yi
- Department of Dermatology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xiayu Li
- Hunan Key Laboratory of Nonresolving Infammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
| | - Hui Wang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
| | - Bo Xiang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China; FuRong Laboratory, Changsha 410078, Hunan, China.
| |
Collapse
|
|
6
|
Salem S, Ashaat E. Association of Relative Telomere Length and LINE-1 Methylation with Autism but not with Severity. J Autism Dev Disord 2024; 54:2266-2273. [PMID: 37014460 PMCID: PMC11142980 DOI: 10.1007/s10803-023-05965-0] [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] [Accepted: 03/10/2023] [Indexed: 04/05/2023]
Abstract
Autism is associated with genomic instability, which is regulated by telomere length (TL) and index of global methylation (LINE-1). This study will determine relative TL (RTL) and LINE-1 methylation percentage for 69 patients and 33 control subjects to evaluate their potential role as biomarkers for autism. The results displayed a significant decrease of both RTL and LINE-1 methylation in autistic cases relative to controls (P < 0.001). Analysis of receiver operating characteristics curve revealed that both of RTL and LINE-1 methylation percentage have the ability to serve as autism biomarkers (area under the curve = 0.817 and 0.889, respectively). The statistical analysis revealed positive correlation between the two biomarkers (correlation coefficient = 0.439 and P < 0.001).
Collapse
Affiliation(s)
- Sohair Salem
- Molecular Genetics & Enzymology Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
| | - Engy Ashaat
- Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
| |
Collapse
|
|
7
|
Li B. Telomere maintenance in African trypanosomes. Front Mol Biosci 2023; 10:1302557. [PMID: 38074093 PMCID: PMC10704157 DOI: 10.3389/fmolb.2023.1302557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 11/15/2023] [Indexed: 02/12/2024] Open
Abstract
Telomere maintenance is essential for genome integrity and chromosome stability in eukaryotic cells harboring linear chromosomes, as telomere forms a specialized structure to mask the natural chromosome ends from DNA damage repair machineries and to prevent nucleolytic degradation of the telomeric DNA. In Trypanosoma brucei and several other microbial pathogens, virulence genes involved in antigenic variation, a key pathogenesis mechanism essential for host immune evasion and long-term infections, are located at subtelomeres, and expression and switching of these major surface antigens are regulated by telomere proteins and the telomere structure. Therefore, understanding telomere maintenance mechanisms and how these pathogens achieve a balance between stability and plasticity at telomere/subtelomere will help develop better means to eradicate human diseases caused by these pathogens. Telomere replication faces several challenges, and the "end replication problem" is a key obstacle that can cause progressive telomere shortening in proliferating cells. To overcome this challenge, most eukaryotes use telomerase to extend the G-rich telomere strand. In addition, a number of telomere proteins use sophisticated mechanisms to coordinate the telomerase-mediated de novo telomere G-strand synthesis and the telomere C-strand fill-in, which has been extensively studied in mammalian cells. However, we recently discovered that trypanosomes lack many telomere proteins identified in its mammalian host that are critical for telomere end processing. Rather, T. brucei uses a unique DNA polymerase, PolIE that belongs to the DNA polymerase A family (E. coli DNA PolI family), to coordinate the telomere G- and C-strand syntheses. In this review, I will first briefly summarize current understanding of telomere end processing in mammals. Subsequently, I will describe PolIE-mediated coordination of telomere G- and C-strand synthesis in T. brucei and implication of this recent discovery.
Collapse
Affiliation(s)
- Bibo Li
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, College of Arts and Sciences, Cleveland State University, Cleveland, OH, United States
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH, United States
| |
Collapse
|
|
8
|
Chaux F, Agier N, Garrido C, Fischer G, Eberhard S, Xu Z. Telomerase-independent survival leads to a mosaic of complex subtelomere rearrangements in Chlamydomonas reinhardtii. Genome Res 2023; 33:1582-1598. [PMID: 37580131 PMCID: PMC10620057 DOI: 10.1101/gr.278043.123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/09/2023] [Indexed: 08/16/2023]
Abstract
Telomeres and subtelomeres, the genomic regions located at chromosome extremities, are essential for genome stability in eukaryotes. In the absence of the canonical maintenance mechanism provided by telomerase, telomere shortening induces genome instability. The landscape of the ensuing genome rearrangements is not accessible by short-read sequencing. Here, we leverage Oxford Nanopore Technologies long-read sequencing to survey the extensive repertoire of genome rearrangements in telomerase mutants of the model green microalga Chlamydomonas reinhardtii In telomerase-mutant strains grown for hundreds of generations, most chromosome extremities were capped by short telomere sequences that were either recruited de novo from other loci or maintained in a telomerase-independent manner. Other extremities did not end with telomeres but only with repeated subtelomeric sequences. The subtelomeric elements, including rDNA, were massively rearranged and involved in breakage-fusion-bridge cycles, translocations, recombinations, and chromosome circularization. These events were established progressively over time and displayed heterogeneity at the subpopulation level. New telomere-capped extremities composed of sequences originating from more internal genomic regions were associated with high DNA methylation, suggesting that de novo heterochromatin formation contributes to the restoration of chromosome end stability in C. reinhardtii The diversity of alternative strategies present in the same organism to maintain chromosome integrity and the variety of rearrangements found in telomerase mutants are remarkable, and illustrate genome plasticity at short timescales.
Collapse
Affiliation(s)
- Frédéric Chaux
- Sorbonne Université, CNRS, UMR7238, Institut de Biologie Paris-Seine, Laboratory of Computational and Quantitative Biology, 75005 Paris, France
| | - Nicolas Agier
- Sorbonne Université, CNRS, UMR7238, Institut de Biologie Paris-Seine, Laboratory of Computational and Quantitative Biology, 75005 Paris, France
| | - Clotilde Garrido
- Sorbonne Université, CNRS, UMR7238, Institut de Biologie Paris-Seine, Laboratory of Computational and Quantitative Biology, 75005 Paris, France
| | - Gilles Fischer
- Sorbonne Université, CNRS, UMR7238, Institut de Biologie Paris-Seine, Laboratory of Computational and Quantitative Biology, 75005 Paris, France
| | - Stephan Eberhard
- Sorbonne Université, CNRS, UMR7141, Institut de Biologie Physico-Chimique, Laboratory of Chloroplast Biology and Light-Sensing in Microalgae, 75005 Paris, France
| | - Zhou Xu
- Sorbonne Université, CNRS, UMR7238, Institut de Biologie Paris-Seine, Laboratory of Computational and Quantitative Biology, 75005 Paris, France;
| |
Collapse
|
|
9
|
Kuse R, Ishii K. Flexible Attachment and Detachment of Centromeres and Telomeres to and from Chromosomes. Biomolecules 2023; 13:1016. [PMID: 37371596 DOI: 10.3390/biom13061016] [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: 05/01/2023] [Revised: 06/15/2023] [Accepted: 06/18/2023] [Indexed: 06/29/2023] Open
Abstract
Accurate transmission of genomic information across multiple cell divisions and generations, without any losses or errors, is fundamental to all living organisms. To achieve this goal, eukaryotes devised chromosomes. Eukaryotic genomes are represented by multiple linear chromosomes in the nucleus, each carrying a centromere in the middle, a telomere at both ends, and multiple origins of replication along the chromosome arms. Although all three of these DNA elements are indispensable for chromosome function, centromeres and telomeres possess the potential to detach from the original chromosome and attach to new chromosomal positions, as evident from the events of telomere fusion, centromere inactivation, telomere healing, and neocentromere formation. These events seem to occur spontaneously in nature but have not yet been elucidated clearly, because they are relatively infrequent and sometimes detrimental. To address this issue, experimental setups have been developed using model organisms such as yeast. In this article, we review some of the key experiments that provide clues as to the extent to which these paradoxical and elusive features of chromosomally indispensable elements may become valuable in the natural context.
Collapse
Affiliation(s)
- Riku Kuse
- Laboratory of Chromosome Function and Regulation, Graduate School of Engineering, Kochi University of Technology, Kochi 782-8502, Japan
| | - Kojiro Ishii
- Laboratory of Chromosome Function and Regulation, Graduate School of Engineering, Kochi University of Technology, Kochi 782-8502, Japan
| |
Collapse
|
|
10
|
Schratz KE, Flasch DA, Atik CC, Cosner ZL, Blackford AL, Yang W, Gable DL, Vellanki PJ, Xiang Z, Gaysinskaya V, Vonderheide RH, Rooper LM, Zhang J, Armanios M. T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers. Cancer Cell 2023; 41:807-817.e6. [PMID: 37037617 PMCID: PMC10188244 DOI: 10.1016/j.ccell.2023.03.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 12/27/2022] [Accepted: 03/06/2023] [Indexed: 04/12/2023]
Abstract
Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed to stem from chromosome instability in neoplastic cells. We tested this hypothesis in a large cohort assembled over the last 20 years. We found that the only solid cancers to which patients with STS are predisposed are squamous cell carcinomas of the head and neck, anus, or skin, a spectrum reminiscent of cancers seen in patients with immunodeficiency. Whole-genome sequencing showed no increase in chromosome instability, such as translocations or chromothripsis. Moreover, STS-associated cancers acquired telomere maintenance mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the immune status of patients with STS revealed a striking T cell immunodeficiency at the time of cancer diagnosis. A similar immunodeficiency that impaired tumor surveillance was documented in mice with short telomeres. We conclude that STS patients’ predisposition to solid cancers is due to T cell exhaustion rather than autonomous defects in the neoplastic cells themselves.
Collapse
Affiliation(s)
- Kristen E Schratz
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Diane A Flasch
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Christine C Atik
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Zoe L Cosner
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Amanda L Blackford
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Wentao Yang
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Dustin L Gable
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Paz J Vellanki
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Zhimin Xiang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Valeriya Gaysinskaya
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Robert H Vonderheide
- Abramson Cancer Center, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Lisa M Rooper
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jinghui Zhang
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Mary Armanios
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
| |
Collapse
|
|
11
|
Telomere length dynamics measured by flow-FISH in patients with obesity undergoing bariatric surgery. Sci Rep 2023; 13:304. [PMID: 36609582 PMCID: PMC9818052 DOI: 10.1038/s41598-022-27196-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 12/28/2022] [Indexed: 01/09/2023] Open
Abstract
Obesity has negative effects on comorbidities, health-related quality of life and survival. Telomere length (TL) changes after bariatric surgery have been reported, but the studies are contradictory, and analyses using state-of-the art techniques for TL measurement, such as flow-FISH, are sparse. We measured TL dynamics via flow-FISH in patients undergoing bariatric surgery and compared their TL with 105 healthy individuals. Patients with obesity who underwent bariatric surgery were included. Lymphocyte and granulocyte absolute and age-adjusted (aa) TL were analyzed by flow-FISH before (preoperative cohort, n = 45) and after surgery (follow-up cohort, n = 35) at month 5.5 ± 3.9 (mean ± standard deviation [SD]). The initial lymphocyte aaTL was significantly shorter (-0.37 kb ± 0.18 kb, P = 0.045) in patients with obesity, while the granulocyte aaTL was not different from that in the healthy comparison population (0.28 kb ± 0.17 kb, P = 0.11). The telomere dynamics after surgery showed an increase in mean TL in both lymphocytes and granulocytes of patients with a pronounced BMI loss of ≥ 10 kg/m2. We did not find any association between TL increase after surgery and age, sex or the type of procedure selected for bariatric surgery. We confirmed that patients suffering from obesity have significantly shorter lymphocyte TL using flow-FISH. Along with and dependent on the degree of weight reduction after bariatric surgery, TL significantly increased in both lymphocytes and granulocytes after a mean of 5.5 months. Our results show that bariatric surgery affects not only body weight but also biomarkers of aging, such as TL.
Collapse
|
|
12
|
Casari E, Gnugnoli M, Rinaldi C, Pizzul P, Colombo CV, Bonetti D, Longhese MP. To Fix or Not to Fix: Maintenance of Chromosome Ends Versus Repair of DNA Double-Strand Breaks. Cells 2022; 11:cells11203224. [PMID: 36291091 PMCID: PMC9601279 DOI: 10.3390/cells11203224] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/07/2022] [Accepted: 10/12/2022] [Indexed: 02/08/2023] Open
Abstract
Early work by Muller and McClintock discovered that the physical ends of linear chromosomes, named telomeres, possess an inherent ability to escape unwarranted fusions. Since then, extensive research has shown that this special feature relies on specialized proteins and structural properties that confer identity to the chromosome ends, thus allowing cells to distinguish them from intrachromosomal DNA double-strand breaks. Due to the inability of conventional DNA replication to fully replicate the chromosome ends and the downregulation of telomerase in most somatic human tissues, telomeres shorten as cells divide and lose this protective capacity. Telomere attrition causes the activation of the DNA damage checkpoint that leads to a cell-cycle arrest and the entering of cells into a nondividing state, called replicative senescence, that acts as a barrier against tumorigenesis. However, downregulation of the checkpoint overcomes this barrier and leads to further genomic instability that, if coupled with re-stabilization of telomeres, can drive tumorigenesis. This review focuses on the key experiments that have been performed in the model organism Saccharomyces cerevisiae to uncover the mechanisms that protect the chromosome ends from eliciting a DNA damage response, the conservation of these pathways in mammals, as well as the consequences of their loss in human cancer.
Collapse
|
|
13
|
Telomeres and Their Neighbors. Genes (Basel) 2022; 13:genes13091663. [PMID: 36140830 PMCID: PMC9498494 DOI: 10.3390/genes13091663] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/21/2022] Open
Abstract
Telomeres are essential structures formed from satellite DNA repeats at the ends of chromosomes in most eukaryotes. Satellite DNA repeat sequences are useful markers for karyotyping, but have a more enigmatic role in the eukaryotic cell. Much work has been done to investigate the structure and arrangement of repetitive DNA elements in classical models with implications for species evolution. Still more is needed until there is a complete picture of the biological function of DNA satellite sequences, particularly when considering non-model organisms. Celebrating Gregor Mendel’s anniversary by going to the roots, this review is designed to inspire and aid new research into telomeres and satellites with a particular focus on non-model organisms and accessible experimental and in silico methods that do not require specialized equipment or expensive materials. We describe how to identify telomere (and satellite) repeats giving many examples of published (and some unpublished) data from these techniques to illustrate the principles behind the experiments. We also present advice on how to perform and analyse such experiments, including details of common pitfalls. Our examples are a selection of recent developments and underexplored areas of research from the past. As a nod to Mendel’s early work, we use many examples from plants and insects, especially as much recent work has expanded beyond the human and yeast models traditional in telomere research. We give a general introduction to the accepted knowledge of telomere and satellite systems and include references to specialized reviews for the interested reader.
Collapse
|
|
14
|
Zhu Y, Gong L, Wei CL. Guilt by association: EcDNA as a mobile transactivator in cancer. Trends Cancer 2022; 8:747-758. [PMID: 35753910 PMCID: PMC9388558 DOI: 10.1016/j.trecan.2022.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/10/2022] [Accepted: 04/28/2022] [Indexed: 10/17/2022]
Abstract
Extrachromosomal DNA (ecDNA), first described in the 1960s, is emerging as a prevalent but poorly characterized oncogenic alteration in cancer. ecDNA is a reservoir for oncogene amplification and is associated with an aggressive tumor phenotype and poor patient outcome. Despite the long-held knowledge of its existence, little is known about how ecDNA affects tumor cell behavior. Recent data reveal that ecDNA hubs are mobile transcriptional enhancers which can transactivate gene expression through chromatin interactions. Given its prevalence, structural complexity, and unequal segregation into daughter cells, ecDNA can offer selective growth advantages, contribute to intratumor heterogeneity (ITH), and accelerate tumor evolution. Future technology development is expected to transform the current paradigm for studying ecDNA and lead to therapeutic strategies targeting ecDNA vulnerabilities.
Collapse
Affiliation(s)
- Yanfen Zhu
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China
| | - Liang Gong
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang 311121, China
| | - Chia-Lin Wei
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
| |
Collapse
|
|
15
|
Global genomic instability caused by reduced expression of DNA polymerase ε in yeast. Proc Natl Acad Sci U S A 2022; 119:e2119588119. [PMID: 35290114 PMCID: PMC8944251 DOI: 10.1073/pnas.2119588119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
SignificanceAlthough most studies of the genetic regulation of genome stability involve an analysis of mutations within the coding sequences of genes required for DNA replication or DNA repair, recent studies in yeast show that reduced levels of wild-type enzymes can also produce a mutator phenotype. By whole-genome sequencing and other methods, we find that reduced levels of the wild-type DNA polymerase ε in yeast greatly increase the rates of mitotic recombination, aneuploidy, and single-base mutations. The observed pattern of genome instability is different from those observed in yeast strains with reduced levels of the other replicative DNA polymerases, Pol α and Pol δ. These observations are relevant to our understanding of cancer and other diseases associated with genetic instability.
Collapse
|
|
16
|
Yang YS, Ning SK, Lyu XH, Suo F, Jia GS, Li W, Du LL. Canavanine resistance mutation can1-1 in Schizosaccharomyces pombe is a missense mutation in the ubiquitin ligase adaptor gene any1. MICROPUBLICATION BIOLOGY 2022; 2022:10.17912/micropub.biology.000538. [PMID: 35300005 PMCID: PMC8922049 DOI: 10.17912/micropub.biology.000538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/05/2022] [Accepted: 03/09/2022] [Indexed: 11/18/2022]
Abstract
In Schizosaccharomyces pombe, the can1-1 mutation confers resistance to the toxic arginine analog canavanine. This mutation has been assumed to disrupt a gene encoding an arginine transporter. In PomBase, the gene SPBC18H10.16 is currently designated can1. Here, we sequenced the genomes of three can1-1 strains. No mutations were found in SPBC18H10.16. Instead, these strains harbor an R175C mutation in the gene any1 (SPBC18H10.20c). any1 encodes an α-arrestin that acts as a ubiquitin ligase adaptor to downregulate plasma membrane amino acid transporters. Our findings indicate that can1-1 is not a loss-of-function mutation in an amino acid transporter gene, but a possible gain-of-function mutation in a gene encoding a negative regulator of amino acid transporters.
Collapse
Affiliation(s)
- Yu-Sheng Yang
- National Institute of Biological Sciences, Beijing, China
| | - Shao-Kai Ning
- National Institute of Biological Sciences, Beijing, China
| | - Xiao-Hui Lyu
- National Institute of Biological Sciences, Beijing, China
| | - Fang Suo
- National Institute of Biological Sciences, Beijing, China
| | - Guo-Song Jia
- National Institute of Biological Sciences, Beijing, China
| | - Wen Li
- National Institute of Biological Sciences, Beijing, China
| | - Li-Lin Du
- National Institute of Biological Sciences, Beijing, China
,
Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
,
Correspondence to: Li-Lin Du (
)
| |
Collapse
|
|
17
|
Kim H, Shin Y, Kim DH. Mechanobiological Implications of Cancer Progression in Space. Front Cell Dev Biol 2021; 9:740009. [PMID: 34957091 PMCID: PMC8692837 DOI: 10.3389/fcell.2021.740009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/18/2021] [Indexed: 12/11/2022] Open
Abstract
The human body is normally adapted to maintain homeostasis in a terrestrial environment. The novel conditions of a space environment introduce challenges that changes the cellular response to its surroundings. Such an alteration causes physical changes in the extracellular microenvironment, inducing the secretion of cytokines such as interleukin-6 (IL-6) and tumor growth factor-β (TGF-β) from cancer cells to enhance cancer malignancy. Cancer is one of the most prominent cell types to be affected by mechanical cues via active interaction with the tumor microenvironment. However, the mechanism by which cancer cells mechanotransduce in the space environment, as well as the influence of this process on human health, have not been fully elucidated. Due to the growing interest in space biology, this article reviews cancer cell responses to the representative conditions altered in space: microgravity, decompression, and irradiation. Interestingly, cytokine and gene expression that assist in tumor survival, invasive phenotypic transformation, and cancer cell proliferation are upregulated when exposed to both simulated and actual space conditions. The necessity of further research on space mechanobiology such as simulating more complex in vivo experiments or finding other mechanical cues that may be encountered during spaceflight are emphasized.
Collapse
Affiliation(s)
- Hyondeog Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea
| | - Yun Shin
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, South Korea
| | - Dong-Hwee Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea.,Department of Integrative Energy Engineering, College of Engineering, Korea University, Seoul, South Korea
| |
Collapse
|
|
18
|
Bellon M, Yuan Y, Nicot C. Transcription Independent Stimulation of Telomerase Enzymatic Activity by HTLV-I Tax Through Stimulation of IKK. JOURNAL OF CANCER SCIENCES 2021; 8. [PMID: 34938859 PMCID: PMC8691565 DOI: 10.13188/2377-9292.1000024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The persistence and spreading of HTLV-I infected cells relies upon their clonal expansion through cellular replication. The development of adult T cell leukemia (ATLL) occurs decades following primary infection by HTLV-I. Moreover, identical provirus integration sites have been found in samples recovered several years apart from infected individuals. These observations suggest that infected cells persist in the host for an extended period of time. To endure long term proliferation, HTLV-I pre-leukemic cells must acquire critical oncogenic events, two of which are the bypassing of apoptosis and replicative senescence. In the early stages of disease, interleukin-2 (IL-2)/IL-2R signaling likely plays a major role in combination with activation of anti-apoptotic pathways. Avoidance of replicative senescence in HTLV-I infected cells is achieved through reactivation of human telomerase (hTERT). We have previously shown that HTLV-I viral Tax transcriptionally activates the hTERT promoter. In this study we demonstrate that Tax can stimulate hTERT enzymatic activity independently of its transcriptional effects. We further show that this occurs through Tax-mediated NF-KB activating functions. Our results suggest that in ATLL cells acquire Tax-transcriptional and post-transcriptional events to elevate telomerase activity.
Collapse
Affiliation(s)
- M Bellon
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, USA
| | - Y Yuan
- Department of Pharmacology, Baylor College of Medicine, USA
| | - C Nicot
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, USA
| |
Collapse
|
|
19
|
Sung JY, Cheong JH. Pan-Cancer Analysis of Clinical Relevance via Telomere Maintenance Mechanism. Int J Mol Sci 2021; 22:ijms222011101. [PMID: 34681758 PMCID: PMC8538844 DOI: 10.3390/ijms222011101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/04/2021] [Accepted: 10/13/2021] [Indexed: 12/24/2022] Open
Abstract
Understanding the telomere maintenance mechanism (TMM) in immortal cancer cells is vital for TMM-targeted therapies in clinical settings. In this study, we classified four telomere maintenance mechanisms into telomerase, ALT, telomerase + ALT, and non-defined telomere maintenance mechanism (NDTMM) across 31 cancer types using 10,704 transcriptomic datasets from The Cancer Genome Atlas. Our results demonstrated that approximately 50% of the total cohort displayed ALT activity with high telomerase activity in most cancer types. We confirmed significant patient prognoses according to distinct TMMs in six cancer types: adrenocortical carcinoma (ACC), PAAD, HNSC, SARC, GBM, and metastatic cancer. Patients with metastasis had a poor prognosis in the ALT group (p < 0.006) subjected to RAS protein signal transduction. Glioblastoma patients had poor prognosis in NDTMM (p < 0.0043) and showed high levels of myeloid leukocyte activation. Pancreatic adenocarcinoma (p < 0.04) and head and neck squamous cell carcinoma (p < 0.046) patients had a good prognosis in the ALT group with high immune cell activation. Furthermore, we showed that master transcriptional regulators might affect the selection of the TMM pathway and explained why different telomere maintenance mechanisms exist. Furthermore, they can be used to segregate patients and predict responders to different TMM-targeted therapeutics.
Collapse
Affiliation(s)
- Ji-Yong Sung
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea;
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jae-Ho Cheong
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea;
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
- Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul 03722, Korea
- Department of Research & Development, VeraVerse Inc., Seoul 03722, Korea
- Correspondence:
| |
Collapse
|
|
20
|
Holland CL, Sanderson BA, Titus JK, Weis MF, Riojas AM, Malczewskyj E, Wasko BM, Lewis LK. Suppression of telomere capping defects of Saccharomyces cerevisiae yku70 and yku80 mutants by telomerase. G3-GENES GENOMES GENETICS 2021; 11:6395363. [PMID: 34718547 PMCID: PMC8664480 DOI: 10.1093/g3journal/jkab359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/27/2021] [Indexed: 11/18/2022]
Abstract
The Ku complex performs multiple functions inside eukaryotic cells, including protection of chromosomal DNA ends from degradation and fusion events, recruitment of telomerase, and repair of double-strand breaks (DSBs). Inactivation of Ku complex genes YKU70 or YKU80 in cells of the yeast Saccharomyces cerevisiae gives rise to mutants that exhibit shortened telomeres and temperature-sensitive growth. In this study, we have investigated the mechanism by which overexpression of telomerase suppresses the temperature sensitivity of yku mutants. Viability of yku cells was restored by overexpression of the Est2 reverse transcriptase and TLC1 RNA template subunits of telomerase, but not the Est1 or Est3 proteins. Overexpression of other telomerase- and telomere-associated proteins (Cdc13, Stn1, Ten1, Rif1, Rif2, Sir3, and Sir4) did not suppress the growth defects of yku70 cells. Mechanistic features of suppression were assessed using several TLC1 RNA deletion derivatives and Est2 enzyme mutants. Supraphysiological levels of three catalytically inactive reverse transcriptase mutants (Est2-D530A, Est2-D670A, and Est2-D671A) suppressed the loss of viability as efficiently as the wild-type Est2 protein, without inducing cell senescence. Roles of proteins regulating telomere length were also determined. The results support a model in which chromosomes in yku mutants are stabilized via a replication-independent mechanism involving structural reinforcement of protective telomere cap structures.
Collapse
Affiliation(s)
- Cory L Holland
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
| | - Brian A Sanderson
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
| | - James K Titus
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
| | - Monica F Weis
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
| | - Angelica M Riojas
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
| | - Eric Malczewskyj
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
| | - Brian M Wasko
- Department of Biology and Biotechnology, University of Houston-Clear Lake, Houston, TX, 77058, USA
| | - L Kevin Lewis
- Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
| |
Collapse
|
|
21
|
Martin H, Doumic M, Teixeira MT, Xu Z. Telomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae. Cell Biosci 2021; 11:180. [PMID: 34627377 PMCID: PMC8502270 DOI: 10.1186/s13578-021-00693-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 09/24/2021] [Indexed: 11/21/2022] Open
Abstract
Background Telomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known. Results Here, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states. Conclusions Replicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-021-00693-3.
Collapse
Affiliation(s)
- Hugo Martin
- JL Lions Laboratory, Sorbonne Université, 75005, Paris, France
| | - Marie Doumic
- JL Lions Laboratory, Sorbonne Université, 75005, Paris, France.
| | - Maria Teresa Teixeira
- Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, PSL, CNRS, UMR8226, Sorbonne Université, 75005, Paris, France
| | - Zhou Xu
- Laboratory of Computational and Quantitative Biology, Institut de Biologie Paris-Seine, CNRS, UMR7238, Sorbonne Université, 75005, Paris, France.
| |
Collapse
|
|
22
|
Huang YC, Wang CY. Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease. Int J Mol Sci 2021; 22:9867. [PMID: 34576030 PMCID: PMC8467562 DOI: 10.3390/ijms22189867] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/31/2021] [Accepted: 09/09/2021] [Indexed: 12/22/2022] Open
Abstract
Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere-CHIP-atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.
Collapse
Affiliation(s)
- Yi-Chun Huang
- Division of Cardiology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City 33305, Taiwan;
| | - Chao-Yung Wang
- Division of Cardiology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City 33305, Taiwan;
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan
- Department of Medical Science, National Tsing Hua University, Hsinchu 30013, Taiwan
| |
Collapse
|
|
23
|
Chaux-Jukic F, O'Donnell S, Craig RJ, Eberhard S, Vallon O, Xu Z. Architecture and evolution of subtelomeres in the unicellular green alga Chlamydomonas reinhardtii. Nucleic Acids Res 2021; 49:7571-7587. [PMID: 34165564 PMCID: PMC8287924 DOI: 10.1093/nar/gkab534] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/01/2021] [Accepted: 06/08/2021] [Indexed: 02/06/2023] Open
Abstract
In most eukaryotes, subtelomeres are dynamic genomic regions populated by multi-copy sequences of different origins, which can promote segmental duplications and chromosomal rearrangements. However, their repetitive nature has complicated the efforts to sequence them, analyse their structure and infer how they evolved. Here, we use recent genome assemblies of Chlamydomonas reinhardtii based on long-read sequencing to comprehensively describe the subtelomere architecture of the 17 chromosomes of this model unicellular green alga. We identify three main repeated elements present at subtelomeres, which we call Sultan, Subtile and Suber, alongside three chromosome extremities with ribosomal DNA as the only identified component of their subtelomeres. The most common architecture, present in 27 out of 34 subtelomeres, is a heterochromatic array of Sultan elements adjacent to the telomere, followed by a transcribed Spacer sequence, a G-rich microsatellite and transposable elements. Sequence similarity analyses suggest that Sultan elements underwent segmental duplications within each subtelomere and rearranged between subtelomeres at a much lower frequency. Analysis of other green algae reveals species-specific repeated elements that are shared across subtelomeres, with an overall organization similar to C. reinhardtii. This work uncovers the complexity and evolution of subtelomere architecture in green algae.
Collapse
Affiliation(s)
- Frédéric Chaux-Jukic
- Sorbonne Université, CNRS, UMR7238, Institut de Biologie Paris-Seine, Laboratory of Computational and Quantitative Biology, 75005 Paris, France
| | - Samuel O'Donnell
- Sorbonne Université, CNRS, UMR7238, Institut de Biologie Paris-Seine, Laboratory of Computational and Quantitative Biology, 75005 Paris, France
| | - Rory J Craig
- Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, EH9 3FL, Edinburgh, UK
| | - Stephan Eberhard
- Sorbonne Université, CNRS, UMR7141, Institut de Biologie Physico-Chimique, Laboratory of Chloroplast Biology and Light-Sensing in Microalgae, 75005 Paris, France
| | - Olivier Vallon
- Sorbonne Université, CNRS, UMR7141, Institut de Biologie Physico-Chimique, Laboratory of Chloroplast Biology and Light-Sensing in Microalgae, 75005 Paris, France
| | - Zhou Xu
- Sorbonne Université, CNRS, UMR7238, Institut de Biologie Paris-Seine, Laboratory of Computational and Quantitative Biology, 75005 Paris, France
| |
Collapse
|
|
24
|
Whitlock B. Telomere Length and Arsenic: Improving Animal Models of Toxicity by Choosing Mice With Shorter Telomeres. Int J Toxicol 2021; 40:211-217. [PMID: 34008434 DOI: 10.1177/10915818211009844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Arsenic is both a chemotherapeutic drug and an environmental toxicant that affects hundreds of millions of people each year. Arsenic exposure in drinking water has been called the worst poisoning in human history. How arsenic is handled in the body is frequently studied using rodent models to investigate how arsenic both causes and treats disease. These models, used in a variety of arsenic-related testing, from tumor formation to drug toxicity monitoring, have virtually always been developed from animals with telomeres that are unnaturally long, likely because of accidental artificial selective pressures. Mice that have been bred in captivity in laboratory conditions, often for over 100 years, are the standard in creating animal models for this research. Using these mice introduces challenges to any work that can be affected by the length of telomeres and the related capacities for tissue repair and cancer resistance. However, arsenic research is particularly susceptible to the misuse of such animal models due to the multiple and various interactions between arsenic and telomeres. Researchers in the field commonly find mouse models and humans behaving very differently upon exposure to acute and chronic arsenic, including drug therapies which seem safe in mice but are toxic in humans. Here, some complexities and apparent contradictions of the arsenic carcinogenicity and toxicity research are reconciled by an explanatory model that involves telomere length explained by the evolutionary pressures in laboratory mice. A low-risk hypothesis is proposed which has the power to determine whether researchers can easily develop more powerful and accurate mouse models by simply avoiding mouse lineages that are very old and have strangely long telomeres. Swapping in newer mouse lineages for the older, long-telomere mice may vastly improve our ability to research arsenic toxicity with virtually no increase in cost or difficulty of research.
Collapse
Affiliation(s)
- Brayden Whitlock
- University of Alberta Health Accelerator, Edmonton, Alberta, Canada.,Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
25
|
Kim E, Kim J, Kim C, Lee J. Long-read sequencing and de novo genome assemblies reveal complex chromosome end structures caused by telomere dysfunction at the single nucleotide level. Nucleic Acids Res 2021; 49:3338-3353. [PMID: 33693840 PMCID: PMC8034613 DOI: 10.1093/nar/gkab141] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/28/2021] [Accepted: 02/20/2021] [Indexed: 02/06/2023] Open
Abstract
Karyotype change and subsequent evolution is triggered by chromosome fusion and rearrangement events, which often occur when telomeres become dysfunctional. Telomeres protect linear chromosome ends from DNA damage responses (DDRs), and telomere dysfunction may result in genome instability. However, the complex chromosome end structures and the other possible consequences of telomere dysfunction have rarely been resolved at the nucleotide level due to the lack of the high-throughput methods needed to analyse these highly repetitive regions. Here we applied long-read sequencing technology to Caenorhabditis elegans survivor lines that emerged after telomere dysfunction. The survivors have preserved traces of DDRs in their genomes and our data revealed that variants generated by telomere dysfunction are accumulated along all chromosomes. The reconstruction of the chromosome end structures through de novo genome assemblies revealed diverse types of telomere damage processing at the nucleotide level. When telomeric repeats were totally eroded by telomere dysfunction, DDRs were mostly terminated by chromosome fusion events. We also partially reconstructed the most complex end structure and its DDR signatures, which would have been accumulated via multiple cell divisions. These finely resolved chromosome end structures suggest possible mechanisms regarding the repair processes after telomere dysfunction, providing insights into chromosome evolution in nature.
Collapse
Affiliation(s)
- Eunkyeong Kim
- Department of Biological Sciences, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Korea.,Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Korea
| | - Jun Kim
- Department of Biological Sciences, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Korea.,Research Institute of Basic Sciences, Seoul National University, Seoul 08826, Korea
| | - Chuna Kim
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Gwahak-ro 125, Daejeon 34141, Korea
| | - Junho Lee
- Department of Biological Sciences, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Korea.,Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Korea.,Research Institute of Basic Sciences, Seoul National University, Seoul 08826, Korea
| |
Collapse
|
|
26
|
Factors Associated with Mutations: Their Matching Rates to Cardiovascular and Neurological Diseases. Int J Mol Sci 2021; 22:ijms22105057. [PMID: 34064609 PMCID: PMC8151074 DOI: 10.3390/ijms22105057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/29/2021] [Accepted: 05/07/2021] [Indexed: 12/28/2022] Open
Abstract
Monogenic hypertension is rare and caused by genetic mutations, but whether factors associated with mutations are disease-specific remains uncertain. Given two factors associated with high mutation rates, we tested how many previously known genes match with (i) proximity to telomeres or (ii) high adenine and thymine content in cardiovascular diseases (CVDs) related to vascular stiffening. We extracted genomic information using a genome data viewer. In human chromosomes, 64 of 79 genetic loci involving >25 rare mutations and single nucleotide polymorphisms satisfied (i) or (ii), resulting in an 81% matching rate. However, this high matching rate was no longer observed as we checked the two factors in genes associated with essential hypertension (EH), thoracic aortic aneurysm (TAA), and congenital heart disease (CHD), resulting in matching rates of 53%, 70%, and 75%, respectively. A matching of telomere proximity or high adenine and thymine content projects the list of loci involving rare mutations of monogenic hypertension better than those of other CVDs, likely due to adoption of rigorous criteria for true-positive signals. Our data suggest that the factor–disease matching rate is an accurate tool that can explain deleterious mutations of monogenic hypertension at a >80% match—unlike the relatively lower matching rates found in human genes of EH, TAA, CHD, and familial Parkinson’s disease.
Collapse
|
|
27
|
Liu Y, Wang J, Huang Z, Liang J, Xia Q, Xia Q, Liu X. Environmental pollutants exposure: A potential contributor for aging and age-related diseases. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 83:103575. [PMID: 33385577 DOI: 10.1016/j.etap.2020.103575] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/13/2020] [Accepted: 12/19/2020] [Indexed: 06/12/2023]
Abstract
Telomeres are "protective messengers" at the ends of eukaryotic chromosomes that protect them from degradation, end to end fusion and recombination. Admittedly, telomeres progressively shorten with age that can also be significantly accelerated by pathological conditions, which are often considered as potential contributors for cellular senescence. It is commonly believed that constant accumulation of senescent cells may lead to dysfunctional tissues and organs, thereby accelerating aging process and subsequent occurrence of age-related diseases. In particular, epidemiological data has indicated a significant association between environmental pollutants exposure and a high incidence of age-related diseases. Moreover, there is growing evidence that environmental toxicity has a detrimental impact on telomere length. Overall, a consensus is emerging that environmental pollutants exposure could lead to accelerated telomere erosion and further induce premature senescence, which may be responsible for the acceleration of aging and the high morbidity and mortality rates of age-related diseases.
Collapse
Affiliation(s)
- Yaru Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui, 230022, China
| | - Jiequan Wang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui, 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui, 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui, 230000, China
| | - Zhaogang Huang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui, 230022, China
| | - Jun Liang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui, 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui, 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui, 230000, China
| | - Qingrong Xia
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui, 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui, 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui, 230000, China
| | - Quan Xia
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui, 230022, China.
| | - Xinhua Liu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
| |
Collapse
|
|
28
|
Zhu XH, Sun BF, Luo M, Yu J, Zhang YD, Xu HQ, Luo H. Bloom helicase explicitly unwinds 3'-tailed G4DNA structure in prostate cancer cells. Int J Biol Macromol 2021; 180:578-589. [PMID: 33727188 DOI: 10.1016/j.ijbiomac.2021.03.060] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 01/22/2021] [Accepted: 03/11/2021] [Indexed: 10/21/2022]
Abstract
G-quadruplex DNA (G4DNA) structure, which widely exists in the chromosomal telomeric regions and oncogenic promoter regions, plays a pivotal role in extending telomeric DNA with the help of telomerase in human cells. Bloom (BLM) helicase, a crucial member of the family of genome surveillance proteins, plays an essential role in DNA metabolic and repair pathways, including DNA replication, repair, transcription, recombination during chromosome segregation, and assuring telomere stability. The unwinding of G4DNA requires the participation of DNA helicase, which is crucial for maintaining chromosomal stability in cancer cells. Using fluorescence polarization and the electrophoretic mobility shift assay (EMSA), this study aimed to investigate the DNA-binding and unwinding properties of BLM helicase, cloned and purified from prostate cancer cells, toward G4DNA. The results revealed that BLM helicase derived from prostate cancer cells could bind and unwind G4DNA. The molecular affinity of bond between G4DNA and the helicase was dependent on the single-stranded DNA (ssDNA) terminals in G4DNA; the helicase was effectively bound to the G4DNA when the helicase monomer sufficiently covered approximately 10 nucleotides at the 3' or 5' ssDNA tail of G4DNA. For the unwinding of G4DNA, there was an apparent requirement of a 3' ssDNA tail and ATP; a G4DNA with only a 3' ssDNA tail was identified to be the most suitable substrate to be unwound by BLM helicase and required 3' ssDNA tails of at least 10 nt in length for efficient unwinding. Besides, BLM helicase was loosely bound and partly unwound the blunt-ended G4DNA. Although further mechanistic studies are warranted, the experimental results presented in this study are beneficial to further our understanding of the functional implication of BLM helicase in prostate cancer cells.
Collapse
Affiliation(s)
- Xu-Hui Zhu
- State Key Laboratory of Functions And Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; Beijing ChaoYang Hospital, Capital Medical University, Beijing 100016, PR China
| | - Bao-Fei Sun
- State Key Laboratory of Functions And Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China
| | - Mei Luo
- State Key Laboratory of Functions And Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Science, Guiyang 550014, PR China
| | - Jia Yu
- State Key Laboratory of Functions And Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Science, Guiyang 550014, PR China
| | | | - Hou-Qiang Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, College of Animal Science, Guizhou University, Guiyang 550025, PR China.
| | - Heng Luo
- State Key Laboratory of Functions And Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Science, Guiyang 550014, PR China; Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, College of Animal Science, Guizhou University, Guiyang 550025, PR China.
| |
Collapse
|
|
29
|
Comez L, Bianchi F, Libera V, Longo M, Petrillo C, Sacchetti F, Sebastiani F, D'Amico F, Rossi B, Gessini A, Masciovecchio C, Amenitsch H, Sissi C, Paciaroni A. Polymorphism of human telomeric quadruplexes with drugs: a multi-technique biophysical study. Phys Chem Chem Phys 2020; 22:11583-11592. [PMID: 32400802 DOI: 10.1039/d0cp01483d] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The human telomeric G-quadruplex structural motif of DNA has come to be known as a new and stimulating target for anticancer drug discovery. Small molecules that interact with G-quadruplex structures in a selective way have gained impressive interest in recent years as they may serve as potential therapeutic agents. Here, we show how circular dichroism, UV resonance Raman and small angle X-ray scattering spectroscopies can be effectively combined to provide insights into structural and molecular aspects of the interaction between human telomeric quadruplexes and ligands. This study focuses on the ability of berberine and palmatine to bind with human telomeric quadruplexes and provides analysis of the conformational landscape visited by the relevant complexes upon thermal unfolding. With increasing temperature, both free and bound G-quadruplexes undergo melting through a multi-state process, populating different intermediate states. Despite the structural similarity of the two ligands, valuable distinctive features characterising their interaction with the G-quadruplex emerged from our multi-technique approach.
Collapse
Affiliation(s)
- L Comez
- IOM-CNR c/o Dipartimento di Fisica e Geologia, Università di Perugia, 06123 Perugia, Italy.
| | - F Bianchi
- Dipartimento di Fisica e Geologia, Università di Perugia, 06123 Perugia, Italy.
| | - V Libera
- Dipartimento di Fisica e Geologia, Università di Perugia, 06123 Perugia, Italy.
| | - M Longo
- JCNS Forschungszentrum Jülich GmbH at Heinz Maier-Leibnitz Zentrum (MLZ), 85748 Garching, Germany
| | - C Petrillo
- Dipartimento di Fisica e Geologia, Università di Perugia, 06123 Perugia, Italy.
| | - F Sacchetti
- Dipartimento di Fisica e Geologia, Università di Perugia, 06123 Perugia, Italy.
| | - F Sebastiani
- Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, 50019 Sesto Fiorentino, FI, Italy
| | - F D'Amico
- Elettra Sincrotrone Trieste, S.S. 14 Km 163.5, 34012 Trieste, Italy
| | - B Rossi
- Elettra Sincrotrone Trieste, S.S. 14 Km 163.5, 34012 Trieste, Italy
| | - A Gessini
- Elettra Sincrotrone Trieste, S.S. 14 Km 163.5, 34012 Trieste, Italy
| | - C Masciovecchio
- Elettra Sincrotrone Trieste, S.S. 14 Km 163.5, 34012 Trieste, Italy
| | - H Amenitsch
- Institute of Inorganic Chemistry, Graz University of Technology, 8010 Graz, Austria
| | - C Sissi
- Dipartimento di Scienze del Farmaco, Via Marzolo 5, 35131 Padova, Italy and Interdepartmental Research Center for Innovative Biotechnologies (CRIBI), University of Padova, University of Padova, Italy
| | - A Paciaroni
- Dipartimento di Fisica e Geologia, Università di Perugia, 06123 Perugia, Italy.
| |
Collapse
|
|
30
|
Li Y, Li J, Guo E, Huang J, Fang G, Chen S, Yang B, Fu Y, Li F, Wang Z, Xiao R, Liu C, Huang Y, Wu X, Lu F, You L, Feng L, Xi L, Wu P, Ma D, Sun C, Wang B, Chen G. Integrating pathology, chromosomal instability and mutations for risk stratification in early-stage endometrioid endometrial carcinoma. Cell Biosci 2020; 10:122. [PMID: 33110489 PMCID: PMC7583263 DOI: 10.1186/s13578-020-00486-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 10/14/2020] [Indexed: 02/06/2023] Open
Abstract
Background Risk stratifications for endometrial carcinoma (EC) depend on histopathology and molecular pathology. Histopathological risk stratification lacks reproducibility, neglects heterogeneity and contributes little to surgical procedures. Existing molecular stratification is useless in patients with specific pathological or molecular characteristics and cannot guide postoperative adjuvant radiotherapies. Chromosomal instability (CIN), the numerical and structural alterations of chromosomes resulting from ongoing errors of chromosome segregation, is an intrinsic biological mechanism for the evolution of different prognostic factors of histopathology and molecular pathology and may be applicable to the risk stratification of EC. Results By analyzing CIN25 and CIN70, two reliable gene expression signatures for CIN, we found that EC with unfavorable prognostic factors of histopathology or molecular pathology had serious CIN. However, the POLE mutant, as a favorable prognostic factor, had elevated CIN signatures, and the CTNNB1 mutant, as an unfavorable prognostic factor, had decreased CIN signatures. Only if these two mutations were excluded were CIN signatures strongly prognostic for outcomes in different adjuvant radiotherapy subgroups. Integrating pathology, CIN signatures and POLE/CTNNB1 mutation stratified stageIendometrioid EC into four groups with improved risk prognostication and treatment recommendations. Conclusions We revealed the possibility of integrating histopathology and molecular pathology by CIN for risk stratification in early-stage EC. Our integrated risk model deserves further improvement and validation.
Collapse
Affiliation(s)
- Yuan Li
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Jiaqi Li
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ensong Guo
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Jia Huang
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Guangguang Fang
- Department of Gynecology,Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen Dapeng New District Maternity & Child Health Hospital, Shenzhen, 518038 China
| | - Shaohua Chen
- Department of Gynecology and Obstetrics, The People's Hospital of Macheng City, Macheng, 438300 China
| | - Bin Yang
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Yu Fu
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Fuxia Li
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Zizhuo Wang
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Rourou Xiao
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Chen Liu
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Yuhan Huang
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Xue Wu
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Funian Lu
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Lixin You
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Ling Feng
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Xi
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Peng Wu
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Ding Ma
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Chaoyang Sun
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Beibei Wang
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| | - Gang Chen
- National Clinical Research Center of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv, Wuhan, 430030 Hubei China
| |
Collapse
|
|
31
|
Bian Y, Song F, Zhang J, Yu J, Wang J, Wang W. Insights into the Kinetic Partitioning Folding Dynamics of the Human Telomeric G-Quadruplex from Molecular Simulations and Machine Learning. J Chem Theory Comput 2020; 16:5936-5947. [PMID: 32794754 DOI: 10.1021/acs.jctc.0c00340] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The human telomeric DNA G-quadruplex follows a kinetic partitioning folding mechanism. The underlying folding landscape potentially has many minima separated by high free-energy barriers. However, using current theoretical models to characterize this complex folding landscape has remained a challenging problem. In this study, by developing a hybrid atomistic structure-based model that merges structural information on the hybrid-1, hybrid-2, and chair-type G-quadruplex topologies, we investigated a kinetic partitioning folding process of human telomeric DNA involving three native folds. The model was validated as it reproduced the experimental observation that the hybrid-1 conformation is the major fold and the hybrid-2 conformation is kinetically more accessible. A three-step mechanism was revealed for the formation of the hybrid-1 conformation, while a two-step mechanism was demonstrated for the formation of hybrid-2 and chair-type conformations. Likewise, a class of state in which structures adopted inappropriate combinations of syn/anti guanine nucleotides was found to greatly slow down the folding process. In addition, by employing the XGBoost machine learning algorithm, three interatom distances and six dihedral angles were identified as essential internal coordinates to represent the low-dimensional folding landscape. The strategy of coupling the multibasin model and the machine learning algorithm may be useful to investigate the conformational dynamics of other multistate biomolecules.
Collapse
Affiliation(s)
- Yunqiang Bian
- Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou 253023, China.,National Laboratory of Solid State Microstructure, Department of Physics, and Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| | - Feng Song
- Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou 253023, China
| | - Jian Zhang
- National Laboratory of Solid State Microstructure, Department of Physics, and Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| | - Jiafeng Yu
- Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou 253023, China
| | - Jihua Wang
- Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou 253023, China
| | - Wei Wang
- National Laboratory of Solid State Microstructure, Department of Physics, and Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| |
Collapse
|
|
32
|
Dahiya R, Mohammad T, Alajmi MF, Rehman MT, Hasan GM, Hussain A, Hassan MI. Insights into the Conserved Regulatory Mechanisms of Human and Yeast Aging. Biomolecules 2020; 10:E882. [PMID: 32526825 PMCID: PMC7355435 DOI: 10.3390/biom10060882] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 05/22/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022] Open
Abstract
Aging represents a significant biological process having strong associations with cancer, diabetes, and neurodegenerative and cardiovascular disorders, which leads to progressive loss of cellular functions and viability. Astonishingly, age-related disorders share several genetic and molecular mechanisms with the normal aging process. Over the last three decades, budding yeast Saccharomyces cerevisiae has emerged as a powerful yet simple model organism for aging research. Genetic approaches using yeast RLS have led to the identification of hundreds of genes impacting lifespan in higher eukaryotes. Numerous interventions to extend yeast lifespan showed an analogous outcome in multi-cellular eukaryotes like fruit flies, nematodes, rodents, and humans. We collected and analyzed a multitude of observations from published literature and provide the contribution of yeast in the understanding of aging hallmarks most applicable to humans. Here, we discuss key pathways and molecular mechanisms that underpin the evolutionarily conserved aging process and summarize the current understanding and clinical applicability of its trajectories. Gathering critical information on aging biology would pave the way for future investigation targeted at the discovery of aging interventions.
Collapse
Affiliation(s)
- Rashmi Dahiya
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India;
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India;
| | - Mohamed F. Alajmi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.F.A.); (M.T.R.); (A.H.)
| | - Md. Tabish Rehman
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.F.A.); (M.T.R.); (A.H.)
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia;
| | - Afzal Hussain
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.F.A.); (M.T.R.); (A.H.)
| | - Md. Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India;
| |
Collapse
|
|
33
|
Saccharomyces cerevisiae Mus81-Mms4 prevents accelerated senescence in telomerase-deficient cells. PLoS Genet 2020; 16:e1008816. [PMID: 32469862 PMCID: PMC7286520 DOI: 10.1371/journal.pgen.1008816] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 06/10/2020] [Accepted: 04/30/2020] [Indexed: 01/31/2023] Open
Abstract
Alternative lengthening of telomeres (ALT) in human cells is a conserved process that is often activated in telomerase-deficient human cancers. This process exploits components of the recombination machinery to extend telomere ends, thus allowing for increased proliferative potential. Human MUS81 (Mus81 in Saccharomyces cerevisiae) is the catalytic subunit of structure-selective endonucleases involved in recombination and has been implicated in the ALT mechanism. However, it is unclear whether MUS81 activity at the telomere is specific to ALT cells or if it is required for more general aspects of telomere stability. In this study, we use S. cerevisiae to evaluate the contribution of the conserved Mus81-Mms4 endonuclease in telomerase-deficient yeast cells that maintain their telomeres by mechanisms akin to human ALT. Similar to human cells, we find that yeast Mus81 readily localizes to telomeres and its activity is important for viability after initial loss of telomerase. Interestingly, our analysis reveals that yeast Mus81 is not required for the survival of cells undergoing recombination-mediated telomere lengthening, i.e. for ALT itself. Rather we infer from genetic analysis that Mus81-Mms4 facilitates telomere replication during times of telomere instability. Furthermore, combining mus81 mutants with mutants of a yeast telomere replication factor, Rrm3, reveals that the two proteins function in parallel to promote normal growth during times of telomere stress. Combined with previous reports, our data can be interpreted in a consistent model in which both yeast and human MUS81-dependent nucleases participate in the recovery of stalled replication forks within telomeric DNA. Furthermore, this process becomes crucial under conditions of additional replication stress, such as telomere replication in telomerase-deficient cells. Cancer cell divisions require active chromosome lengthening through extension of their highly repetitive ends, called telomeres. This process is accomplished through two main mechanisms: the activity of an RNA-protein complex, telomerase, or through a telomerase-independent process termed alternative lengthening of telomeres (ALT). Human MUS81, the catalytic subunit of a set of structure-selective endonucleases, was found to be essential in human cells undergoing ALT and proposed to be directly involved in telomere lengthening. Using telomerase-deficient Saccharomyces cerevisiae cells as a model for ALT, we tested the hypothesis that Mus81-Mms4, the budding yeast homolog of human MUS81-dependent nucleases, is essential for telomere lengthening as proposed for human cells. Using genetic and molecular assays we confirm that Mus81-Mms4 is involved in telomere metabolism in yeast. However, to our surprise, we find that Mus81-Mms4 is not directly involved in recombination-based mechanisms of telomere lengthening. Rather it appears that Mus81-Mms4 is involved in resolving replication stress at telomeres, which is augmented in cells undergoing telomere instability. This model is consistent with observations in mammalian cells and suggest that cells undergoing telomere shortening experience replication stress at telomeres.
Collapse
|
|
34
|
Telomere lengths differ significantly between small-cell neuroendocrine prostate carcinoma and adenocarcinoma of the prostate. Hum Pathol 2020; 101:70-79. [PMID: 32389660 DOI: 10.1016/j.humpath.2020.04.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/19/2020] [Accepted: 04/28/2020] [Indexed: 01/05/2023]
Abstract
Small-cell neuroendocrine carcinoma (SCNC) of the prostate is an aggressive subtype with frequent TP53 mutation and RB1 inactivation; however, the molecular phenotype remains an area of investigation. Here, we compared telomere lengths in prostatic SCNC and usual-type prostatic adenocarcinoma (AdCa). We studied 32 cases of prostatic SCNC (including 11 cases with concurrent AdCa) and 347 cases of usual-type AdCa on tissue microarrays. Telomere lengths in tumor cells were qualitatively compared with those in normal cells using a telomere-specific fluorescence in situ hybridization assay. ERG, PTEN, and TP53 status were assessed in a proportion of cases using genetically validated immunohistochemistry protocols. Clinicopathological and molecular characteristics of cases were compared between the telomere groups using the chi-square test.A significantly higher proportion of prostatic SCNC cases (50%, 16/32) showed normal/long telomeres compared with AdCa cases (11%, 39/347; P < 0.0001). In 82% (9/11) of cases with concurrent SCNC and AdCa, the paired components were concordant for telomere length status. Among AdCa cases, the proportion of cases with normal/long telomeres significantly increased with increasing tumor grade group (P = 0.01) and pathologic stage (P = 0.02). Cases with normal/long telomeres were more likely to be ERG positive (P = 0.04) and to have TP53 missense mutation (P = 0.01) than cases with short telomeres.Normal or long telomere lengths are significantly more common in prostatic SCNC than in AdCa and are similar between concurrent SCNC and AdCa tumors, supporting a common origin. Among AdCa cases, longer telomere lengths are significantly associated with high-risk pathologic and molecular features.
Collapse
|
|
35
|
Langston RE, Palazzola D, Bonnell E, Wellinger RJ, Weinert T. Loss of Cdc13 causes genome instability by a deficiency in replication-dependent telomere capping. PLoS Genet 2020; 16:e1008733. [PMID: 32287268 PMCID: PMC7205313 DOI: 10.1371/journal.pgen.1008733] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 05/07/2020] [Accepted: 03/23/2020] [Indexed: 01/02/2023] Open
Abstract
In budding yeast, Cdc13, Stn1, and Ten1 form the telomere-binding heterotrimer CST complex. Here we investigate the role of Cdc13/CST in maintaining genome stability by using a Chr VII disome system that can generate recombinants, chromosome loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitive CDC13 allele, cdc13F684S, unstable chromosomes frequently arise from problems in or near a telomere. We found that, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes that are then the source for additional chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or chromosome loss). We observed that genome instability arises from a defect in Cdc13’s function during DNA replication, not Cdc13’s putative post-replication telomere capping function. The molecular nature of the initial unstable chromosomes formed by a Cdc13-defect involves ssDNA and does not involve homologous recombination nor non-homologous end joining; we speculate the original unstable chromosome may be a one-ended double strand break. This system defines a link between Cdc13’s function during DNA replication and genome stability in the form of unstable chromosomes, that then progress to form other chromosome changes. Eukaryotic chromosomes are linear molecules with specialized end structures called telomeres. Telomeres contain both unique repetitive DNA sequences and specialized proteins that solve several biological problems by differentiating chromosomal ends from internal breaks, thus preventing chromosome instability. When telomeres are defective, the entire chromosome can become unstable and change, causing mutations and pathology (cancer, aging, etc.). Here we study how a defect in specific telomere proteins causes chromosomal rearrangements, using the model organism Saccharomyces cerevisiae (budding or brewer’s yeast). We find that when specific telomere proteins are defective, errors in DNA replication generate a type of damage that likely involves extensive single-stranded DNA that forms inherently unstable chromosomes, subject to many subsequent instances of instability (e.g. allelic recombinants, chromosome loss, truncations, dicentrics). The telomere protein Cdc13 is part of a protein complex called CST that is conserved in most organisms including mammalian cells. The technical capacity of studies in budding yeast allow a detailed, real-time examination of how telomere defects compromise chromosome stability in a single cell cycle, generating lessons likely relevant to how human telomeres keep human chromosomes stable.
Collapse
Affiliation(s)
- Rachel E. Langston
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America
| | - Dominic Palazzola
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America
| | - Erin Bonnell
- Department of Microbiology and Infectiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Raymund J. Wellinger
- Department of Microbiology and Infectiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Ted Weinert
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America
- * E-mail:
| |
Collapse
|
|
36
|
Henninger E, Teixeira MT. Telomere-driven mutational processes in yeast. Curr Opin Genet Dev 2020; 60:99-106. [DOI: 10.1016/j.gde.2020.02.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 02/13/2020] [Accepted: 02/14/2020] [Indexed: 12/18/2022]
|
|
37
|
Biswas S, Samui S, Das AK, Pasadi S, Muniyappa K, Naskar J. Targeting G-quadruplex DNA with synthetic dendritic peptide: modulation of the proliferation of human cancer cells. RSC Adv 2020; 10:26388-26396. [PMID: 35685402 PMCID: PMC9122626 DOI: 10.1039/d0ra04780e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 06/30/2020] [Indexed: 01/04/2023] Open
Abstract
Telomerase, a reverse transcriptase enzyme, is found to over express in most cancer cells. It elongates the telomere region by repeated adding of TTAGGG in the 3′-end and leads to excess cell proliferation which causes cancer. G-quadruplex (G4) formation can inhibit such telomere lengthening. So, stabilization of G4 structure as well as inhibition of telomerase activity is very promising approach in targeted cancer therapy. Herein, the aptitude of a synthetic dendritic peptide, Cδ2–(YEE)–E (peptide 1), to target specifically the human telomeric G4 DNA, dAGGG(TTAGGG)3, has been evaluated. Both biochemical and biophysical techniques including gel mobility shift assay, isothermal titration calorimetry and fluorescence spectroscopy have been employed for the purpose. Circular dichroism study reveals that the targeting results an increase in thermal stability of G4 DNA. Interestingly, replacement of N-terminal tyrosine residue of peptide 1 by valine, Cδ2–(VEE)–E, (peptide 2) consequences in loss of its G4 DNA targeting ability, although both the peptides exhibit comparable affinity toward double-stranded DNA. Of note, peptide 1 causes cessation of growth of human cancer cells (HeLa and U2OS) and induces apoptosis in vitro. But it has no significant inhibitory effect on the growth of normal human embryonic kidney 293 cells. Mechanistically, Telomeric Repeat Amplification Protocol (TRAP) assay indicates that peptide 1 effectively inhibits the telomerase activity in human cell extracts. Overall, this study demonstrates the usefulness of a synthetic dendritic peptide as an inhibitor of tumor cell growth by inducing apoptosis upon targeting the telomeric G4 DNA. A synthetic dendritic peptide, targeting human telomeric G4 DNA, inhibits the telomerase and lessens the proliferation of human cancer cells.![]()
Collapse
Affiliation(s)
- Soumi Biswas
- Department of Biochemistry and Biophysics
- University of Kalyani
- Nadia
- India
| | - Satyabrata Samui
- Department of Biochemistry and Biophysics
- University of Kalyani
- Nadia
- India
| | - Apurba K. Das
- Department of Chemistry
- Indian Institute of Technology Indore
- Indore 453552
- India
| | - Sanjeev Pasadi
- Department of Biochemistry
- Indian Institute of Science
- Bangalore
- India
| | - K. Muniyappa
- Department of Biochemistry
- Indian Institute of Science
- Bangalore
- India
| | - Jishu Naskar
- Department of Biochemistry and Biophysics
- University of Kalyani
- Nadia
- India
| |
Collapse
|
|
38
|
Yeh JK, Lin MH, Wang CY. Telomeres as Therapeutic Targets in Heart Disease. ACTA ACUST UNITED AC 2019; 4:855-865. [PMID: 31998853 PMCID: PMC6978555 DOI: 10.1016/j.jacbts.2019.05.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/27/2019] [Accepted: 05/28/2019] [Indexed: 12/14/2022]
Abstract
Age-associated CVDs impose a great burden on current health systems. Despite the fact that current strong evidence supports the links among aging, telomere attrition, and CVDs, there is no clear direction for the development of telomere therapeutics against CVDs. This review focuses on immune modulation, CHIP, pharmaceutical interventions, and gene therapy for their therapeutic roles in age-associated CVDs. The future goal of telomere cardiovascular therapy in young subjects is to prevent senescence and diseases, whereas in older adult subjects, the goal is restoration of cardiovascular functions. Further studies on the telomere-CHIP-atherosclerosis axis may shed insights on how to achieve these 2 different therapeutic targets. Telomeres are double-stranded repeats of G-rich tandem DNA sequences that gradually shorten with each cell division. Aging, inflammation, and oxidative stress accelerate the process of telomere shortening. Telomerase counteracts this process by maintaining and elongating the telomere length. Patients with atherosclerotic diseases and cardiovascular risk factors (e.g., smoking, obesity, sedentary lifestyle, and hypertension) have shorter leukocyte telomere length. Following myocardial infarction, telomerase expression and activity in cardiomyocytes and endothelial cells increase significantly, implying that telomerase plays a role in regulating tissue repairs in heart diseases. Although previous studies have focused on the changes of telomeres in heart diseases and the telomere length as a marker for aging cardiovascular systems, recent studies have explored the potential of telomeres and telomerase in the treatment of cardiovascular diseases. This review discusses the significant advancements of telomere therapeutics in gene therapy, atherosclerosis, anti-inflammation, and immune modulation in patients with cardiovascular diseases.
Collapse
Affiliation(s)
- Jih-Kai Yeh
- Department of Cardiology, Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Taoyuan City, Taiwan
| | - Mei-Hsiu Lin
- Department of Cardiology, Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Taoyuan City, Taiwan
| | - Chao-Yung Wang
- Department of Cardiology, Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Taoyuan City, Taiwan.,Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
| |
Collapse
|
|
39
|
Xu Z, Teixeira MT. The many types of heterogeneity in replicative senescence. Yeast 2019; 36:637-648. [PMID: 31306505 PMCID: PMC6900063 DOI: 10.1002/yea.3433] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/04/2019] [Accepted: 07/07/2019] [Indexed: 11/10/2022] Open
Abstract
Replicative senescence, which is induced by telomere shortening, underlies the loss of regeneration capacity of organs and is ultimately detrimental to the organism. At the same time, it is required to protect organisms from unlimited cell proliferation that may arise from numerous stimuli or deregulations. One important feature of replicative senescence is its high level of heterogeneity and asynchrony, which promote genome instability and senescence escape. Characterizing this heterogeneity and investigating its sources are thus critical to understanding the robustness of replicative senescence. Here we review the different aspects of senescence driven by telomere attrition that are subject to variation in Saccharomyces cerevisiae, the current understanding of the molecular processes at play, and the consequences of heterogeneity in replicative senescence.
Collapse
Affiliation(s)
- Zhou Xu
- CNRS, UMR7238, Institut de Biologie Paris‐Seine, Laboratory of Computational and Quantitative BiologySorbonne UniversitéParisFrance
| | - Maria Teresa Teixeira
- CNRS, UMR8226, Institut de Biologie Physico‐Chimique, Laboratory of Molecular and Cell Biology of EukaryotesSorbonne Université, PSL Research UniversityParisFrance
| |
Collapse
|
|
40
|
Pompili L, Maresca C, Dello Stritto A, Biroccio A, Salvati E. BRCA2 Deletion Induces Alternative Lengthening of Telomeres in Telomerase Positive Colon Cancer Cells. Genes (Basel) 2019; 10:genes10090697. [PMID: 31510074 PMCID: PMC6771010 DOI: 10.3390/genes10090697] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/16/2019] [Accepted: 09/03/2019] [Indexed: 11/25/2022] Open
Abstract
BRCA1/2 are tumor suppressor genes controlling genomic stability also at telomeric and subtelomeric loci. Their mutation confers a predisposition to different human cancers but also sensitivity to antitumor drugs including poly(ADP-ribose) polymerase (PARP) inhibitors and G-quadruplex stabilizers. Here we demonstrate that BRCA2 deletion triggers TERRA hyperexpression and alternative lengthening mechanisms (ALT) in colon cancer cells in presence of telomerase activity. This finding opens the question if cancer patients bearing BRCA2 germline or sporadic mutation are suitable for anti-telomerase therapies, or how ALT activation could influence the short or long-term response to anti-PARP inhibitors or anti-G-quadruplex therapies.
Collapse
Affiliation(s)
- Luca Pompili
- Oncogenomic and Epigenetic Unit, IRCSS Regina Elena National Cancer Institute, Via Elio Chianesi, 53-00144 Rome, Italy.
| | - Carmen Maresca
- Oncogenomic and Epigenetic Unit, IRCSS Regina Elena National Cancer Institute, Via Elio Chianesi, 53-00144 Rome, Italy.
| | - Angela Dello Stritto
- Biology and Biotechnology Department "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro, 5-00185 Rome, Italy.
| | - Annamaria Biroccio
- Oncogenomic and Epigenetic Unit, IRCSS Regina Elena National Cancer Institute, Via Elio Chianesi, 53-00144 Rome, Italy.
| | - Erica Salvati
- Oncogenomic and Epigenetic Unit, IRCSS Regina Elena National Cancer Institute, Via Elio Chianesi, 53-00144 Rome, Italy.
- Institute of Molecular Biology and Pathology, CNR, Via degli Apuli, 4-00185 Rome, Italy.
| |
Collapse
|
|
41
|
Günes C, Wezel F, Southgate J, Bolenz C. Implications of TERT promoter mutations and telomerase activity in urothelial carcinogenesis. Nat Rev Urol 2019; 15:386-393. [PMID: 29599449 DOI: 10.1038/s41585-018-0001-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Telomerase activity imparts eukaryotic cells with unlimited proliferation capacity, one of the cancer hallmarks. Over 90% of human urothelial carcinoma of the bladder (UCB) tumours are positive for telomerase activity. Telomerase activation can occur through several mechanisms. Mutations in the core promoter region of the human telomerase reverse transcriptase gene (TERT) cause telomerase reactivation in 60-80% of UCBs, whereas the prevalence of these mutations is lower in urothelial cancers of other origins. TERT promoter mutations are the most frequent genetic alteration across all stages of UCB, indicating a strong selection pressure during neoplastic transformation. TERT promoter mutations could arise during regeneration of normal urothelium and, owing to consequential telomerase reactivation, might be the basis of UCB initiation, which represents a new model of urothelial cancer origination. In the future, TERT promoter mutations and telomerase activity might have diagnostic and therapeutic applications in UCB.
Collapse
Affiliation(s)
- Cagatay Günes
- Department of Urology, University of Ulm, Ulm, Germany.
| | - Felix Wezel
- Department of Urology, University of Ulm, Ulm, Germany
| | - Jennifer Southgate
- Department of Biology, Jack Birch Unit of Molecular Carcinogenesis, University of York, York, UK
| | | |
Collapse
|
|
42
|
Essential Saccharomyces cerevisiae genome instability suppressing genes identify potential human tumor suppressors. Proc Natl Acad Sci U S A 2019; 116:17377-17382. [PMID: 31409704 DOI: 10.1073/pnas.1906921116] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Gross Chromosomal Rearrangements (GCRs) play an important role in human diseases, including cancer. Although most of the nonessential Genome Instability Suppressing (GIS) genes in Saccharomyces cerevisiae are known, the essential genes in which mutations can cause increased GCR rates are not well understood. Here 2 S. cerevisiae GCR assays were used to screen a targeted collection of temperature-sensitive mutants to identify mutations that caused increased GCR rates. This identified 94 essential GIS (eGIS) genes in which mutations cause increased GCR rates and 38 candidate eGIS genes that encode eGIS1 protein-interacting or family member proteins. Analysis of TCGA data using the human genes predicted to encode the proteins and protein complexes implicated by the S. cerevisiae eGIS genes revealed a significant enrichment of mutations affecting predicted human eGIS genes in 10 of the 16 cancers analyzed.
Collapse
|
|
43
|
Maekawa T, Liu B, Nakai D, Yoshida K, Nakamura KI, Yasukawa M, Koike M, Takubo K, Chatton B, Ishikawa F, Masutomi K, Ishii S. ATF7 mediates TNF-α-induced telomere shortening. Nucleic Acids Res 2019; 46:4487-4504. [PMID: 29490055 PMCID: PMC5961373 DOI: 10.1093/nar/gky155] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 02/20/2018] [Indexed: 12/23/2022] Open
Abstract
Telomeres maintain the integrity of chromosome ends and telomere length is an important marker of aging. The epidemiological studies suggested that many types of stress including psychosocial stress decrease telomere length. However, it remains unknown how various stresses induce telomere shortening. Here, we report that the stress-responsive transcription factor ATF7 mediates TNF-α–induced telomere shortening. ATF7 and telomerase, an enzyme that elongates telomeres, are localized on telomeres via interactions with the Ku complex. In response to TNF-α, which is induced by various stresses including psychological stress, ATF7 was phosphorylated by p38, leading to the release of ATF7 and telomerase from telomeres. Thus, a decrease of ATF7 and telomerase on telomeres in response to stress causes telomere shortening, as observed in ATF7-deficient mice. These findings give credence to the idea that various types of stress might shorten telomere.
Collapse
Affiliation(s)
- Toshio Maekawa
- Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
| | - Binbin Liu
- Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.,Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan
| | - Daisuke Nakai
- Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.,Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan
| | - Keisuke Yoshida
- Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
| | - Ken-Ichi Nakamura
- Research Team for Geriatric Diseases, Tokyo Metropolitan Institute of Gerontology, Sakaecho 35-2, Itabashi-ku, Tokyo 173-0015, Japan
| | - Mami Yasukawa
- Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan
| | - Manabu Koike
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Kaiyo Takubo
- Research Team for Geriatric Diseases, Tokyo Metropolitan Institute of Gerontology, Sakaecho 35-2, Itabashi-ku, Tokyo 173-0015, Japan
| | - Bruno Chatton
- Université de Strasbourg, UMR7242 Biotechnologie et Signalisation Cellulaire, Ecole Supérieure de Biotechnologie de Strasbourg, BP10413, Illkirch, France
| | - Fuyuki Ishikawa
- Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Kenkichi Masutomi
- Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan
| | - Shunsuke Ishii
- Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.,Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan
| |
Collapse
|
|
44
|
Gong P, Wang H, Zhang J, Fu Y, Zhu Z, Wang J, Yin Y, Wang H, Zhou Z, Yang J, Liu L, Gou M, Zeng M, Yuan J, Wang F, Pan X, Xiang R, Weissman SM, Qi F, Liu L. Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer. Transl Oncol 2019; 12:1164-1176. [PMID: 31207547 PMCID: PMC6580093 DOI: 10.1016/j.tranon.2019.05.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 05/13/2019] [Indexed: 02/06/2023] Open
Abstract
Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.
Collapse
Affiliation(s)
- Peng Gong
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Hua Wang
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jingsong Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yudong Fu
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Zhengmao Zhu
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jinmiao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yu Yin
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Haiying Wang
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Zhongcheng Zhou
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jiao Yang
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Linlin Liu
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Mo Gou
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Ming Zeng
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jinghua Yuan
- Department of Genetics, Tianjin Medical University, Tianjin, 300070, China
| | - Feng Wang
- Department of Genetics, Tianjin Medical University, Tianjin, 300070, China
| | - Xinghua Pan
- Department of Genetics, Yale School of Medicine, New Haven, CT, 06520, USA
| | - Rong Xiang
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy
| | - Sherman M Weissman
- Department of Genetics, Yale School of Medicine, New Haven, CT, 06520, USA
| | - Feng Qi
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - Lin Liu
- State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.
| |
Collapse
|
|
45
|
Wu G, Chen L, Liu W, Yang D. Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres. Molecules 2019; 24:molecules24081578. [PMID: 31013622 PMCID: PMC6514847 DOI: 10.3390/molecules24081578] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 04/17/2019] [Accepted: 04/19/2019] [Indexed: 12/13/2022] Open
Abstract
G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.
Collapse
Affiliation(s)
- Guanhui Wu
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 W Stadium Ave, West Lafayette, IN 47907, USA.
| | - Luying Chen
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 W Stadium Ave, West Lafayette, IN 47907, USA.
| | - Wenting Liu
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 W Stadium Ave, West Lafayette, IN 47907, USA.
| | - Danzhou Yang
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 W Stadium Ave, West Lafayette, IN 47907, USA.
- Purdue Center for Cancer Research, 201 S University St, West Lafayette, IN 47906, USA.
- Purdue Institute for Drug Discovery, 720 Clinic Dr, West Lafayette, IN 47907, USA.
| |
Collapse
|
|
46
|
Reilly NM, Novara L, Di Nicolantonio F, Bardelli A. Exploiting DNA repair defects in colorectal cancer. Mol Oncol 2019; 13:681-700. [PMID: 30714316 PMCID: PMC6441925 DOI: 10.1002/1878-0261.12467] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/11/2019] [Accepted: 01/19/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC. At present, only immune checkpoint blockade therapies have been FDA approved for use in mismatch repair-deficient colorectal tumors. Here, we discuss how systematic identification of alterations in DNA repair genes could provide new therapeutic opportunities for CRCs. Analysis of The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) and Rectal Adenocarcinoma (TCGA-READ) PanCancer Atlas datasets identified 141 (out of 528) cases with putative driver mutations in 29 genes associated with DNA damage response and repair, including the mismatch repair and homologous recombination pathways. Genetic defects in these pathways might confer repair-deficient characteristics, such as genomic instability in the absence of homologous recombination, which can be exploited. For example, inhibitors of poly(ADP)-ribose polymerase are effectively used to treat cancers that carry mutations in BRCA1 and/or BRCA2 and have shown promising results in CRC preclinical studies. HR deficiency can also occur in cells with no detectable BRCA1/BRCA2 mutations but exhibiting BRCA-like phenotypes. DNA repair-targeting therapies, such as ATR and CHK1 inhibitors (which are most effective against cancers carrying ATM mutations), can be used in combination with current genotoxic chemotherapies in CRCs to further improve therapy response. Finally, therapies that target alternative DNA repair mechanisms, such as thiopurines, also have the potential to confer increased sensitivity to current chemotherapy regimens, thus expanding the spectrum of therapy options and potentially improving clinical outcomes for CRC patients.
Collapse
Affiliation(s)
- Nicole M. Reilly
- Fondazione Piemontese per la Ricerca sul Cancro ONLUSCandioloItaly
| | - Luca Novara
- Candiolo Cancer InstituteFPO‐IRCCSCandioloItaly
| | - Federica Di Nicolantonio
- Candiolo Cancer InstituteFPO‐IRCCSCandioloItaly
- Department of OncologyUniversity of TorinoCandioloItaly
| | - Alberto Bardelli
- Candiolo Cancer InstituteFPO‐IRCCSCandioloItaly
- Department of OncologyUniversity of TorinoCandioloItaly
| |
Collapse
|
|
47
|
Pellestor F. Chromoanagenesis: cataclysms behind complex chromosomal rearrangements. Mol Cytogenet 2019; 12:6. [PMID: 30805029 PMCID: PMC6371609 DOI: 10.1186/s13039-019-0415-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 01/17/2019] [Indexed: 12/21/2022] Open
Abstract
Background During the last decade, genome sequencing projects in cancer genomes as well as in patients with congenital diseases and healthy individuals have led to the identification of new types of massive chromosomal rearrangements arising during single chaotic cellular events. These unanticipated catastrophic phenomenon are termed chromothripsis, chromoanasynthesis and chromoplexis., and are grouped under the name of “chromoanagenesis”. Results For each process, several specific features have been described, allowing each phenomenon to be distinguished from each other and to understand its mechanism of formation and to better understand its aetiology. Thus, chromothripsis derives from chromosome shattering followed by the random restitching of chromosomal fragments with low copy-number change whereas chromoanasynthesis results from erroneous DNA replication of a chromosome through serial fork stalling and template switching with variable copy-number gains, and chromoplexy refers to the occurrence of multiple inter-and intra-chromosomal translocations and deletions with little or no copy-number alterations in prostate cancer. Cumulating data and experimental models have shown that chromothripsis and chromoanasynthesis may essentially result from lagging chromosome encapsulated in micronuclei or telomere attrition and end-to-end telomere fusion. Conclusion The concept of chromanagenesis has provided new insight into the aetiology of complex structural rearrangements, the connection between defective cell cycle progression and genomic instability, and the complexity of cancer evolution. Increasing reported chromoanagenesis events suggest that these chaotic mechanisms are probably much more frequent than anticipated.
Collapse
Affiliation(s)
- Franck Pellestor
- Unit of Chromosomal Genetics, Department of Medical Genetics, Arnaud de Villeneuve Hospital, Montpellier CHRU, 371, avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 5, France.,INSERM 1183 Unit «Genome and Stem Cell Plasticity in Development and Aging », Institute of Regenerative Medicine and Biotherapies, St Eloi Hospital, Montpellier, France
| |
Collapse
|
|
48
|
Li Y, Xiang C, Shen N, Deng L, Luo X, Yuan P, Ji Z, Li J, Cheng L. Functional polymorphisms on chromosome 5p15.33 disturb telomere biology and confer the risk of non‐small cell lung cancer in Chinese population. Mol Carcinog 2019; 58:913-921. [DOI: 10.1002/mc.22980] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 01/10/2019] [Accepted: 01/18/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Ying Li
- Department of Laboratory MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Cheng Xiang
- Department of Laboratory MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Na Shen
- Department of Laboratory MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Lingyan Deng
- Department of Laboratory MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xia Luo
- Department of Laboratory MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Peihong Yuan
- Department of Laboratory MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Zhi Ji
- Department of Laboratory MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jiaoyuan Li
- Department of Laboratory MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Liming Cheng
- Department of Laboratory MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| |
Collapse
|
|
49
|
Ballester B, Milara J, Cortijo J. Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets. Int J Mol Sci 2019; 20:ijms20030593. [PMID: 30704051 PMCID: PMC6387034 DOI: 10.3390/ijms20030593] [Citation(s) in RCA: 210] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/18/2019] [Accepted: 01/28/2019] [Indexed: 12/18/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 2–4 years after diagnosis. A significant number of IPF patients have risk factors, such as a history of smoking or concomitant emphysema, both of which can predispose the patient to lung cancer (LC) (mostly non-small cell lung cancer (NSCLC)). In fact, IPF itself increases the risk of LC development by 7% to 20%. In this regard, there are multiple common genetic, molecular, and cellular processes that connect lung fibrosis with LC, such as myofibroblast/mesenchymal transition, myofibroblast activation and uncontrolled proliferation, endoplasmic reticulum stress, alterations of growth factors expression, oxidative stress, and large genetic and epigenetic variations that can predispose the patient to develop IPF and LC. The current approved IPF therapies, pirfenidone and nintedanib, are also active in LC. In fact, nintedanib is approved as a second line treatment in NSCLC, and pirfenidone has shown anti-neoplastic effects in preclinical studies. In this review, we focus on the current knowledge on the mechanisms implicated in the development of LC in patients with IPF as well as in current IPF and LC-IPF candidate therapies based on novel molecular advances.
Collapse
Affiliation(s)
- Beatriz Ballester
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
- CIBERES, Health Institute Carlos III, 28029 Valencia, Spain.
| | - Javier Milara
- CIBERES, Health Institute Carlos III, 28029 Valencia, Spain.
- Pharmacy Unit, University Clinic Hospital of Valencia, 46010 Valencia, Spain.
- Institute of Health Research-INCLIVA, 46010 Valencia, Spain.
| | - Julio Cortijo
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
- CIBERES, Health Institute Carlos III, 28029 Valencia, Spain.
- Research and teaching Unit, University General Hospital Consortium, 46014 Valencia, Spain.
| |
Collapse
|
|
50
|
Henry MP, Hawkins JR, Boyle J, Bridger JM. The Genomic Health of Human Pluripotent Stem Cells: Genomic Instability and the Consequences on Nuclear Organization. Front Genet 2019; 9:623. [PMID: 30719030 PMCID: PMC6348275 DOI: 10.3389/fgene.2018.00623] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 11/23/2018] [Indexed: 12/11/2022] Open
Abstract
Human pluripotent stem cells (hPSCs) are increasingly used for cell-based regenerative therapies worldwide, with embryonic and induced pluripotent stem cells as potential treatments for debilitating and chronic conditions, such as age-related macular degeneration, Parkinson's disease, spinal cord injuries, and type 1 diabetes. However, with the level of genomic anomalies stem cells generate in culture, their safety may be in question. Specifically, hPSCs frequently acquire chromosomal abnormalities, often with gains or losses of whole chromosomes. This review discusses how important it is to efficiently and sensitively detect hPSC aneuploidies, to understand how these aneuploidies arise, consider the consequences for the cell, and indeed the individual to whom aneuploid cells may be administered.
Collapse
Affiliation(s)
- Marianne P Henry
- Advanced Therapies Division, National Institute for Biological Standards and Control, Potters Bar, United Kingdom.,Laboratory of Nuclear and Genomic Health, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom
| | - J Ross Hawkins
- Advanced Therapies Division, National Institute for Biological Standards and Control, Potters Bar, United Kingdom
| | - Jennifer Boyle
- Advanced Therapies Division, National Institute for Biological Standards and Control, Potters Bar, United Kingdom
| | - Joanna M Bridger
- Laboratory of Nuclear and Genomic Health, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom
| |
Collapse
|