Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence
Open accessAbstract
Genomic instability is a hallmark of aging tissues. Genomic instability may arise from the inefficient or aberrant function of DNA double-stranded break (DSB) repair. DSBs are repaired by homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). HR is a precise pathway, whereas NHEJ frequently leads to deletions or insertions at the repair site. Here, we used normal human fibroblasts with a chromosomally integrated HR reporter cassette to examine the changes in HR efficiency as cells progress to replicative senescence. We show that HR declines sharply with increasing replicative age, with an up to 38-fold decrease in efficiency in presenescent cells relative to young cells. This decline is not explained by a reduction of the number of cells in S/G 2 /M stage as presenescent cells are actively dividing. Expression of proteins involved in HR such as Rad51, Rad51C, Rad52, NBS1, and Sirtuin 6 (SIRT6) diminished with cellular senescence. Supplementation of Rad51, Rad51C, Rad52, and NBS1 proteins, either individually or in combination, did not rescue the senescence-related decline of HR. However, overexpression of SIRT6 in “middle-aged” and presenescent cells strongly stimulated HR repair, and this effect was dependent on mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). These results suggest that in aging cells, the precise HR pathway becomes repressed giving way to a more error-prone NHEJ pathway. These changes in the processing of DSBs may contribute to age-related genomic instability and a higher incidence of cancer with age. SIRT6 activation provides a potential therapeutic strategy to prevent the decline in genome maintenance.
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Most DNA repair factors are downregulated in senescent cells, decreasing repair activity, especially homologous repair.
“Most DNA repair factors are downregulated in senescent cells resulting in decreased repair activity, especially homologous repair pathway activity (Mao et al., 2012; Seluanov et al., 2004).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Mao et al., 2012
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- Authors
- Mao, Z., Tian, X., Van Meter, M., Ke, Z., Gorbunova, V., & Seluanov, A.
- Affiliations
- University of Rochester (US)
- University of California, San Francisco (US)
- Department of Biology, University of Rochester, Rochester, NY 14627
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-07-02
- Volume
- 109
- Issue
- 29
- Pages
- 11800-11805
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3406824
- OpenAlex
- W2092010310
- Cited by
- 176
- References
- 39
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 12 · 2023: 6 · 2022: 10 · 2021: 16 · 2020: 9 · 2019: 18 · 2018: 13 · 2017: 17 · 2016: 22 · 2015: 20 · 2014: 8 · 2013: 13 · 2012: 1
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- National Institutes of Health
- National Institute on Aging (F31AG041603, R01AG027237)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- SIRT6, homologous recombination repair, replicative senescence, genomic instability, aging, DNA double-strand break repair, non-homologous end joining, PARP1, mono-ADP-ribosylation, RAD51, NBS1, RAD51C, RAD52, human fibroblasts, age-related cancer risk
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Age Factors, Cell Line, Fibroblasts, Flow Cytometry, Fluorescent Antibody Technique, Humans, Poly(ADP-ribose) Polymerases, Polymerase Chain Reaction, Cellular Senescence, Sirtuins, Genomic Instability, DNA Breaks, Double-Stranded, Homologous Recombination
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