Protecting the Aging Genome

Trends in Cell Biology, Journal Year: 2020, Volume and Issue: 30(2), P. 117 - 132

Published: Jan. 6, 2020

DNA damage accumulates with aging.Defects in repair lead to premature aging.Emerging drugs that target may alleviate age-associated phenotypes. Mounting evidence suggests plays a central role aging. Multiple tiers of defense have evolved reduce the accumulation damage, including reducing damaging molecules, repairing and inducing senescence or apoptosis response persistent damage. Mutations failure these pathways can accelerated aging age-related decline vital organs, supporting hypothesis maintaining pristine genome is paramount for human health. Understanding how we cope could inform on process further deficient maintenance manifests This knowledge development novel interventions promoting healthspan. endogenous exogenous molecules chemically modify our DNA. To deal stressors, cells developed ways production of, eliminate, before occurs (Box 1), once it occurs, eliminate accumulated too much (Figure 1). These three are focus this review. The most well-described mechanism toxic antioxidant removal reactive oxygen species (ROS) they react other such as DNA, proteins, lipids. In addition, oxidized lipids proteins form adducts [1Chung F.-L. et al.Deoxyguanosine t-4-hydroxy-2-nonenal lesions rodents humans: detection potential sources.Cancer Res. 2000; 60: 1507-1511PubMed Google Scholar,2Niedernhofer L.J. al.Malondialdehyde, product lipid peroxidation, mutagenic cells.J. Biol. Chem. 2003; 278: 31426-31433Crossref PubMed Scopus (0) Scholar]. Nonenzymatic antioxidants glutathione vitamin C E well enzymes superoxide dismutase, catalase, peroxidases attempt counter protect genome. If first tier fails, coordinate processes reverse return its undamaged (functional) state. highly conserved mechanisms be classified into following pathways: direct reversal, base excision repair, nucleotide double-strand break interstrand crosslink 2).Box 1Endogenous Sources DamageOxidative stress not only metabolic byproduct Complex occur by multitude processes. For example, acetaldehyde, formed acetyl metabolism after alcohol consumption, readily reacts forming variety single-base crosslinks [165Langevin F. al.Fancd2 counteracts effects naturally produced aldehydes mice.Nature. 2011; 475: 53-58Crossref (271) An important way through enzymatic acetaldehyde enzyme dehydrogenase converts molecule acetate. Accordingly, point mutations ALDH2 gene encodes increased susceptibility alcohol-induced cancers [166Chang J.S. al.ALDH2 polymorphism alcohol-related Asians: public health perspective.J. Biomed. Sci. 2017; 24: 19Crossref (35) Interestingly, dehydrogenation reversible equilibrium pointing heavily towards alcohol, levels, even case intoxication, hover micromolar range while ethanol concentrations remain 100-fold higher. Conversely, acetate essentially irreversible levels reach millimolar during intoxication. Thus, biochemical minimize amount present perhaps limit genotoxic effect metabolites.Another source methylation facilitated S-adenosylmethionine (SAM). SAM an acts physiological donor various reactions CpG island thereby regulating expression. However, also nonenzymatically induce methyl [167Macintyre G. al.Lowering Escherichia coli modulates C-to-T transition mutations.J. Bacteriol. 2001; 183: 921-927Crossref Scholar,168Posnick L.M. Samson L.D. Influence pool size spontaneous mutation, dam methylation, cell growth coli.J. 1999; 181: 6756-6762Crossref Scholar] need repaired reversal pathway indicated Box 2. synthesized from methionine adenosine dietary restriction has been shown [169Mentch S.J. al.Histone dynamics regulation sensing one-carbon metabolism.Cell Metab. 2015; 22: 861-873Abstract Full Text PDF (155) extend lifespan multiple organisms [170Ables G.P. Johnson J.E. Pleiotropic responses restriction.Exp. Gerontol. 94: 83-88Crossref (21) One speculative thus mutagenesis lowering phenomenon observed bacteria decreasing increases Drosophila Caenorhabditis elegans lifespans [171Obata Miura M. Enhancing S-adenosyl-methionine catabolism extends lifespan.Nat. Commun. 6: 8332Crossref (32) Scholar,172Hansen al.New genes tied endocrine, metabolic, genomic RNAi screen.PLoS Genet. 2005; 1: 119-128Crossref (327) Scholar].In sum, removing their absence dysfunction pathologies associated aging.Box 2Mammalian Repair PathwaysDNA general three-step process: detection, removal, resynthesis new I). Direct deals simple modifications without altering backbone primarily used DNA-alkylating agents. two major types proteins: O6-methylguanine-DNA methyltransferases (MGMTs) using single reaction where group transferred MGMT protein inactivating it; via AlkB dioxygenases iron-catalyzed multistep reaction. brain, lung, bladder cancer risk [173Martínez-Ramírez O.C. al.Association promoter rs12917 formation bulky lung Mexican mestizo population.DNA Cell 2019; 38: 307-313Crossref (1) Scholar,174Cetica V. al.Pediatric brain tumors: (hABH2 hABH3) directly alkylation damage.J. Neurooncol. 2009; 195-201Crossref (20) due nature O6-methylguanine lesion.Base damaged recognized removed one, short-patch several, long-patch bases added instead. Defects commonly linked neurodegeneration [175Krokan H.E. Bjørås Base repair.Cold Spring Harb. Perspect. 2013; 5: a012583Crossref (322) Scholar], aging.Mismatch misincorporated replication post-replicative synthesis part pathways. classic genetic mismatch disease Lynch syndrome accumulate rapidly proliferating gastrointestinal tract resulting high colon [26Sinicrope F.A. syndrome-associated colorectal cancer.N. Engl. J. Med. 2018; 379: 764-773Crossref Scholar].Nucleotide corrects bulkier and/or helix-distorting lesions, often caused UV irradiation, require piece single-stranded oligonucleotide, containing patients inherited defects suffer sun sensitivity skin [111Bradford P.T. al.Cancer neurologic degeneration xeroderma pigmentosum: long term follow-up characterises repair.J. 48: 168-176Crossref (207) Scholar,176Cleaver Defective pigmentosum.Nature. 1968; 218: 652-656Crossref (1180) short stature common features, although pathogenesis particular traits still debated [177Cleaver al.Disorders repair: molecular basis heterogeneity.Nat. Rev. 10: 756-768Crossref Scholar].Homologous recombination one breaks. relies homologous chromosomes S G2/M phase cycle. steps involve break, resection 5′ end invasion sister chromatid which elongation invaded allow bridging area was broken. Inherited deficiency list phenotypes neurodegeneration, microcephaly, ionizing radiation sensitivity, stature, cancer, anemia, immune deficiency, skeletal defects, pigmentation changes, hypogonadism [125Woods C.G. Taylor A.M. Ataxia telangiectasia British Isles: clinical laboratory features 70 affected individuals.Q. 1992; 82: 169-179PubMed Scholar,178Qvist P. al.CtIP cause Seckel Jawad syndromes.PLoS 7: e1002310Crossref Scholar].A second attempts correct breaks nonhomologous joining. entails no, very minor, followed ligation ends. deficiencies joining prominently immunodeficiency at antibody loci. display cardiovascular disease, [119Buck D. al.Cernunnos, end-joining factor, mutated microcephaly.Cell. 2006; 124: 287-299Abstract (506) Scholar].One complex crosslink, complementary strands covalently connected. Here, lesion detected strand incised each side allowing crosslinked flipped out helix what called unhooking step. Resynthesis translesion polymerase allows gap. Subsequent unhooked done repair. typically results Fanconi affects bone marrow eventually leading pancytopenia [27Auerbach A.D. al.International Anemia Registry: relation symptoms diepoxybutane sensitivity.Blood. 1989; 73: 391-396Crossref anemia changes [143Korgaonkar S. al.Clinical, cytogenetic study Indian population.Hematology. 2010; 15: 58-62Crossref (10) Scholar,179Giri N. al.Endocrine abnormalities anemia.J. Clin. Endocrinol. 2007; 92: 2624-2631Crossref (92) Scholar].Figure IDifferent Pathways Deal Different Lesions.Show full captionDirect events. guanine oxidation. Nucleotide 6–4 photoproducts cyclopyrimidine dimers. Interstrand required both strands. A plethora different pathways.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Oxidative metabolites. Another lesion. Mismatch Homologous association between established extensive data humans animal models showing markers instability age [3Dollé M.E. al.Rapid rearrangements liver but old mice.Nat. 1997; 17: 431-434Crossref Scholar,4Sedelnikova O.A. al.Senescing ageing mice unrepairable breaks.Nat. 2004; 168-170Crossref (499) possible reason increase capacity decrease [5Moriwaki al.The processing UV-damaged cultured cells: reduced mutability.Mutat. 1996; 364: 117-123Crossref Scholar, 6Mayer P.J. al.Age-dependent rejoining X-ray-induced normal lymphocytes.Mutat. 219: 95-100Crossref 7Krichevsky al.Age related microsatellite T healthy individuals.Exp. 39: 507-515Crossref 8Imam S.Z. al.Mitochondrial nuclear DNA-repair regions mouse altered age-dependent manner.Neurobiol. Aging. 27: 1129-1136Crossref (134) Markers diseases dementias, suggesting causal factor [9Myung N.-H. al.Evidence Alzheimer disease: phosphorylation histone H2AX astrocytes.Age (Dordr.). 2008; 30: 209-215Crossref 10Botto coronary artery disease.Mutat. 493: 23-30Crossref 11Negrini al.Genomic – evolving hallmark cancer.Nat. Mol. 11: 220-228Crossref (1007) compelling observation some show 2) [12Keijzers al.Monogenic repair.N. 377: 1868-1876Crossref Scholar,13Hoeijmakers J.H.J. aging, 361: 1475-1485Crossref (1013) Importantly, tissues. individuals Cockayne ataxia-telangiectasia neurological [14Wilson B.T. Syndrome Natural History (CoSyNH) study: findings 102 recommendations care.Genet. 2016; 18: 483-493Abstract (43) Scholar,15Shiloh Y. Lederman H.M. Ataxia-telangiectasia (A-T): emerging dimension ageing.Ageing 33: 76-88Crossref Werner Hutchinson–Gilford progeria [16Muftuoglu characteristics syndrome: diagnosis.Hum. 369-377Crossref Scholar,17Merideth M.A. al.Phenotype course syndrome.N. 358: 592-604Crossref (356) Due significant heterogeneity diseases, impact outside none perfectly phenocopies segmental progerias. More than 50 disorders described degrees overlapping neurodegen

Language: Английский

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ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Cancers, Journal Year: 2020, Volume and Issue: 12(3), P. 687 - 687

Published: March 14, 2020

Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations breast and ovarian cancer susceptibility genes BRCA1 BRCA2, with many more potential applications under study clinical trials. Here, we discuss for extending PARP inhibitor therapies to tumours deficiencies DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that inhibition alone is cytostatic but not cytotoxic ATM-deficient cells combination a an ATR (ATM, Rad3-related) required induce cell death.

Language: Английский

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DNA damage and mitochondria in cancer and aging

Carcinogenesis, Journal Year: 2020, Volume and Issue: 41(12), P. 1625 - 1634

Published: Oct. 28, 2020

Abstract Age and DNA repair deficiencies are strong risk factors for developing cancer. This is reflected in the comorbidity of cancer with premature aging diseases associated damage deficiencies. Recent research has suggested that accumulation, telomere dysfunction accompanying mitochondrial exacerbate process may increase development. Thus, an area interest both elucidation dynamic crosstalk between nucleus mitochondria. In this review, we discuss current on specific focus role as well how nuclear to signaling be a driving factor increased incidence aging. We suggest therapeutic interventions aimed at induction autophagy mediation provide mechanism healthier reduced tumorigenesis.

Language: Английский

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Inhibition of the cGAS‐STING pathway ameliorates the premature senescence hallmarks of Ataxia‐Telangiectasia brain organoids

Aging Cell, Journal Year: 2021, Volume and Issue: 20(9)

Published: Aug. 30, 2021

Ataxia-telangiectasia (A-T) is a genetic disorder caused by the lack of functional ATM kinase. A-T characterized chronic inflammation, neurodegeneration and premature ageing features that are associated with increased genome instability, nuclear shape alterations, micronuclei accumulation, neuronal defects entry into cellular senescence. The causal relationship between detrimental inflammatory signature neurological deficiencies remains elusive. Here, we utilize human pluripotent stem cell-derived cortical brain organoids to study neuropathology. Mechanistically, show cGAS-STING pathway required for recognition induction senescence-associated secretory phenotype (SASP) in olfactory neurosphere-derived cells organoids. We further demonstrate cGAS STING inhibition effectively suppresses self-DNA-triggered SASP expression organoids, inhibits astrocyte senescence neurodegeneration, ameliorates organoid Our thus reveals activity an important contributor inflammation central nervous system constitutes novel therapeutic target treating neuropathology patients.

Language: Английский

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Cell stretching activates an ATM mechano-transduction pathway that remodels cytoskeleton and chromatin

Cell Reports, Journal Year: 2023, Volume and Issue: 42(12), P. 113555 - 113555

Published: Dec. 1, 2023

Ataxia telangiectasia mutated (ATM) and ataxia Rad3-related (ATR) DNA damage response (DDR) kinases contain elastic domains. ATM also responds to reactive oxygen species (ROS) ATR nuclear mechanical stress. Mre11 mediates activation following damage; mutations cause (A-T). Here, using in vivo imaging, electron microscopy, proteomic, mechano-biology approaches, we study how We report that cytoskeleton ROS, but not Mre11, mediate cell deformation. deficiency causes hyper-stiffness, stress fiber accumulation, Yes-associated protein (YAP) enrichment, plasma membrane alterations during interstitial migration, H3 hyper-methylation. locates the actin and, stress, promotes phosphorylation of key chromatin regulators. Our data contribute explain some clinical features patients with A-T pinpoint existence an integrated mechano-response which have distinct roles unrelated their canonical DDR functions.

Language: Английский

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Replication stress as a driver of cellular senescence and aging

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: May 22, 2024

Abstract Replication stress refers to slowing or stalling of replication fork progression during DNA synthesis that disrupts faithful copying the genome. While long considered a nexus for damage, role in aging is under-appreciated. The consequential promotion organismal phenotypes evidenced by an extensive list hereditary accelerated disorders marked molecular defects factors promote and operate uniquely response. Additionally, recent studies have revealed cellular pathways elicited align with designated hallmarks aging. Here we review advances demonstrating as ultimate driver senescence We discuss clinical implications intriguing links between including application senotherapeutic approaches context stress.

Language: Английский

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ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies

Blood, Journal Year: 2024, Volume and Issue: 144(11), P. 1193 - 1205

Published: June 25, 2024

Language: Английский

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The cGAS–STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(2)

Published: Jan. 7, 2025

Ataxia–telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of homeostatic protein kinase ATM. The complex phenotype A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts patients exhibit senescence, highlighting association between cellular We found that derived ATM-deficient mice provide versatile experimental system to explore mechanisms driving senescence primary lacking Atm −/− failed proliferate under ambient oxygen conditions (21%). Although they initially proliferated physiological levels (3%), rapidly entered senescence. In contrast, wild-type (WT) did not senesce 3% eventually underwent immortalization neoplastic transformation. However, rapid could be induced in WT cells either by gene ablation or persistent chemical inhibition ATM activity, with being reversible upon inhibitor removal. Moreover, concomitant p53 led evasion, vigorous growth, rampant subsequent Our findings reveal driven collaborative action cGAS–STING, p38 MAPK, pathways response DNA damage, ultimately leading induction interferon-α1 downstream interferon-stimulated genes. propose accelerated may exacerbate specific symptoms, particularly contributing progressive, life-threatening disease often observed during adulthood.

Language: Английский

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Neurodegeneration in ataxia‐telangiectasia: Multiple roles of ATM kinase in cellular homeostasis

Developmental Dynamics, Journal Year: 2017, Volume and Issue: 247(1), P. 33 - 46

Published: May 23, 2017

Ataxia‐telangiectasia (A‐T) is characterized by neuronal degeneration, cancer, diabetes, immune deficiency, and increased sensitivity to ionizing radiation. A‐T attributed the deficiency of protein kinase coded ATM (ataxia‐telangiectasia mutated) gene. a sensor DNA double‐strand breaks (DSBs) signals cell cycle checkpoints repair machinery. phosphorylates numerous substrates activates many cell‐signaling pathways. There has been considerable debate about whether defective damage response causative neurological aspects disease. In proliferating cells, localized mainly in nucleus; however, postmitotic cells such as neurons, mostly cytoplasmic. Recent studies reveal an increasing number roles for cytoplasm, including activation oxidative stress. associates with organelles mitochondria peroxisomes, both sources reactive oxygen species (ROS), which have implicated neurodegenerative diseases aging. also associated synaptic vesicles role regulating cellular homeostasis autophagy. The cytoplasmic provide new perspective on process A‐T. This review will examine expanding relate these functions complex phenotype. Developmental Dynamics 247:33–46, 2018 . © 2017 Wiley Periodicals, Inc.

Language: Английский

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Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria

eLife, Journal Year: 2018, Volume and Issue: 7

Published: May 2, 2018

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered response (DDR) progressively declines senescence age, while low dose of chloroquine (CQ) activates ATM, clearance, rescues age-related metabolic shift, prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase thus prevents MDM2-mediated ubiquitination proteasomal degradation. Extra copies Sirt6 extend lifespan in Atm-/- mice, restored homeostasis. Moreover, the treatment CQ remarkably extends Caenorhabditis elegans, but not ATM-1 mutants. In a progeria mouse model capacity, long-term administration ameliorates premature aging features Thus, our data highlights pro-longevity role for first time establishing direct causal links between longevity, providing therapeutic strategy diseases.

Language: Английский

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