Do DNA Double-Strand Breaks Drive Aging?

White, Ryan R.; Vijg, Jan

doi:10.1016/j.molcel.2016.08.004

Cited by 186 publications

(154 citation statements)

References 98 publications

Supporting

Mentioning

150

Contrasting

Order By: Relevance

“…In humans, there is an abundance of evidence linking DNA damage to aging, including cancer chemotherapy, radiation exposure, smoking, and progeroid diseases such as Werner and Cockayne's syndrome (Hofstatter et al, 2018;Horvath and Levine, 2015;Maccormick, 2006;Nance and Berry, 1992;Salk et al, 1985). Similarly, in model organisms, deficiencies in DNA repair, such as Ercc1, BubR1, Ku70, and Xpd mutant mice, also appear to accelerate aspects of aging (Carrero et al, 2016;White and Vijg, 2016). But mutation accumulation as a main cause of aging has been hard to reconcile with other findings that nuclear mutations in old individuals are not only rarer than would be expected, they can occur with high frequency without causing signs of aging (Dolle et al, 2006;Dolle et al, 1997;Narayanan et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

Hayano

Yang

Bonkowski

et al. 2019

Preprint

View full text Add to dashboard Cite

SUMMARYThere are numerous hallmarks of aging in mammals, but no unifying cause has been identified. In budding yeast, aging is associated with a loss of epigenetic information that occurs in response to genome instability, particularly DNA double-strand breaks (DSBs). Mammals also undergo predictable epigenetic changes with age, including alterations to DNA methylation patterns that serve as epigenetic “age” clocks, but what drives these changes is not known. Using a transgenic mouse system called “ICE” (for inducible changes to the epigenome), we show that a tissue’s response to non-mutagenic DSBs reorganizes the epigenome and accelerates physiological, cognitive, and molecular changes normally seen in older mice, including advancement of the epigenetic clock. These findings implicate DSB-induced epigenetic drift as a conserved cause of aging from yeast to mammals.One Sentence SummaryDNA breaks induce epigenomic changes that accelerate the aging clock in mammals

show abstract

Section: Discussionmentioning

confidence: 99%

DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

Hayano

Yang

Bonkowski

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The latter is accomplished in part by ATP-dependent chromatin remodelers, whose activity directly affects access to DSBs and influences repair pathway selection (Jeggo and Downs, 2014;Price and D'Andrea, 2013). Given that defects in DSB repair are a direct cause of cancers, immune disorders, and age-related diseases in humans, the role of chromatin remodelers in these contexts has been the subject of numerous recent investigations (Alt et al, 2013;Raschellà et al, 2017;So et al, 2017;Tubbs and Nussenzweig, 2017;White and Vijg, 2016). In spite of their importance, however, the mechanisms by which chromatin modifiers coordinate DSB repair are meiotically-dividing cells is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

et al. 2018

View full text Add to dashboard Cite

Meiotic recombination depends upon the tightly coordinated regulation of chromosome dynamics and is essential for the production of haploid gametes. Central to this process is the formation and repair of meiotic double-stranded breaks (DSBs), which must take place within the constraints of a specialized chromatin architecture. Here, we demonstrate a role for the nucleosome remodeling and deacetylase (NuRD) complex in orchestrating meiotic chromosome dynamics in Caenorhabditis elegans. Our data reveal that the conserved Mi2 homologs Chromodomain helicase DNA binding protein (CHD-3) and its paralog LET-418 facilitate meiotic progression by ensuring faithful repair of DSBs through homologous recombination. We discovered that loss of either CHD-3 or LET-418 results in elevated p53-dependent germline apoptosis, which relies on the activation of the conserved checkpoint kinase CHK-1. Consistent with these findings, chd-3 and let-418 mutants produce a reduced number of offspring, indicating a role for Mi2 in forming viable gametes. When Mi2 function is compromised, persisting recombination intermediates are detected in late pachytene nuclei, indicating a failure in the timely repair of DSBs. Intriguingly, our data indicate that in Mi2 mutant germ lines, a subset of DSBs are repaired by non-homologous end joining, which manifests as chromosomal fusions.We find that meiotic defects are exacerbated in Mi2 mutants lacking CKU-80, as evidenced by increased recombination intermediates, corpses, and defects in chromosomal integrity. Taken together, our findings support a model wherein the C. elegans Mi2 complex maintains genomic integrity through reinforcement of a chromatin landscape suitable for homology-driven repair mechanisms.4

show abstract

“…We therefore set out to examine whether an impairment in DNA repair capacity contributes to the loss of genome integrity. Since mounting evidence indicates that the efficiency of two DNA DSB repair pathways—NHEJ and HR declines with age in somatic cells in both mice and human beings (Li et al, ; Vaidya et al, ) and that deficiency in NHEJ or HR pathway leads to a phenotype of premature aging (Espejel et al, ; White & Vijg, ), we therefore first examined if NHEJ or HR changed with age in human ADSCs using our well‐characterized, GFP‐based reporter cassettes (Li et al, ; Mao et al, ). We linearized NHEJ or HR reporter cassettes with the restriction enzyme, I‐SceI, in vitro and then transfected the digested NHEJ (0.6 µg) or HR (1.5 µg) reporter constructs together with 0.03 µg pCMV‐DsRed2, for normalizing transfection efficiency, into each exponentially proliferating ADSC line at a concentration of 8 × 10 5 cells/ transfection.…”

Section: Introduction Results and Discussionmentioning

confidence: 99%

Section: Introduction Re Sults and Discussionmentioning

confidence: 99%

Base excision repair but not DNA double‐strand break repair is impaired in aged human adipose‐derived stem cells

et al. 2019

View full text Add to dashboard Cite

The decline in DNA repair capacity contributes to the age-associated decrease in genome integrity in somatic cells of different species. However, due to the lack of clinical samples and appropriate tools for studying DNA repair, whether and how age-associated changes in DNA repair result in a loss of genome integrity of human adult stem cells remains incompletely characterized. Here, we isolated 20 eyelid adipose-derived stem cell (ADSC) lines from healthy individuals (young: 10 donors with ages ranging 17-25 years; old: 10 donors with ages ranging 50-59 years). Using these cell lines, we systematically compared the efficiency of base excision repair (BER) and two DNA double-strand break (DSB) repair pathways-nonhomologous end joining (NHEJ) and homologous recombination (HR)-between the young and old groups.Surprisingly, we found that the efficiency of BER but not NHEJ or HR is impaired in aged human ADSCs, which is in contrast to previous findings that DSB repair declines with age in human fibroblasts. We also demonstrated that BER efficiency is negatively associated with tail moment, which reflects a loss of genome integrity in human ADSCs. Mechanistic studies indicated that at the protein level XRCC1, but not other BER factors, exhibited age-associated decline. Overexpression of XRCC1 reversed the decline of BER efficiency and genome integrity, indicating that XRCC1 is a potential therapeutic target for stabilizing genomes in aged ADSCs. K E Y W O R D Sadipose-derived stem cells, base excision repair, genome integrity, human aging, XRCC1

show abstract

Do DNA Double-Strand Breaks Drive Aging?

Cited by 186 publications

References 98 publications

DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

Base excision repair but not DNA double‐strand break repair is impaired in aged human adipose‐derived stem cells

Contact Info

Product

Resources

About