Delayed kinetics of DNA double‐strand break processing in normal and pathological aging
Open accessAbstract
Summary: Accumulation of DNA damage may play an essential role in both cellular senescence and organismal aging. The ability of cells to sense and repair DNA damage declines with age. However, the underlying molecular mechanism for this age‐dependent decline is still elusive. To understand quantitative and qualitative changes in the DNA damage response during human aging, DNA damage‐induced foci of phosphorylated histone H2AX (γ‐H2AX), which occurs specifically at sites of DNA double‐strand breaks (DSBs) and eroded telomeres, were examined in human young and senescing fibroblasts, and in lymphocytes of peripheral blood. Here, we show that the incidence of endogenous γ‐H2AX foci increases with age. Fibroblasts taken from patients with Werner syndrome, a disorder associated with premature aging, genomic instability and increased incidence of cancer, exhibited considerably higher incidence of γ‐H2AX foci than those taken from normal donors of comparable age. Further increases in γ‐H2AX focal incidence occurred in culture as both normal and Werner syndrome fibroblasts progressed toward senescence. The rates of recruitment of DSB repair proteins to γ‐H2AX foci correlated inversely with age for both normal and Werner syndrome donors, perhaps due in part to the slower growth of γ‐H2AX foci in older donors. Because genomic stability may depend on the efficient processing of DSBs, and hence the rapid formation of γ‐H2AX foci and the rapid accumulation of DSB repair proteins on these foci at sites of nascent DSBs, our findings suggest that decreasing efficiency in these processes may contribute to genome instability associated with normal and pathological aging.
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As growth rate slows, the frequency of dysmorphic nuclei increases as does the number with γ-H2AX foci in HGPS/RD cells.
“As the growth rate slows the frequency of dysmorphic nuclei increases as does the number with γ-H2AX (a marker of DNA DSBs) foci detected by immunofluorescence microscopy [11,19,37].”
From Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A (2009) · cites this paper as [37]
The level of γ-H2AX increases with an individual's age in tissue samples and with time in culture for primary cell explants, concomitant with a parallel increase in laminopathy-induced DNA damage and pathological changes in nuclear morphology and chromatin structures.
“For instance, the level of γ-H2AX increases with an individual's age in tissue samples and with time in culture for primary cell explants [21,37,39], which is concomitant with a parallel increase in laminopathy-induced DNA damage and the pathological changes in nuclear morphology and chromatin structures.”
From Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A (2009) · cites this paper as [37]
Correlation with telomere shortening is corroborated by accumulation of γ-H2AX foci in cells of older donors and patients with progeria.
“Correlation with telomere shortening is corroborated by accumulation of γ-H2AX foci in cells of older donors and patients with progeria [82-84, 86-88].”
From Markers of cellular senescence. Telomere shortening as a marker of cellular senescence (2016) · cites this paper as [88]
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- Authors
- Sedelnikova, O. A., Horikawa, I., Redon, C., Nakamura, A., Zimonjic, D. B., Popescu, N. C., & Bonner, W. M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Sedelnikova, Olga A.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2007-11-13
- Volume
- 7
- Issue
- 1
- Pages
- 89-100
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- OpenAlex
- W2145004994
- Cited by
- 207
- References
- 9
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 7 · 2023: 7 · 2022: 10 · 2021: 14 · 2020: 5 · 2019: 8 · 2018: 12 · 2017: 11 · 2016: 19 · 2015: 15 · 2014: 14 · 2013: 12 · 2012: 14
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- DNA double-strand break repair, DNA damage response, γH2AX foci, Werner syndrome, cellular senescence, biological aging, genomic instability, telomeres, lymphocytes, fibroblasts, premature aging
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, MRE11 Homologue Protein, Adult, Aging, Cells, Cultured, DNA Repair, DNA-Binding Proteins, Fibroblasts, Gamma Rays, Histones, Humans, Kinetics, Lymphocytes, Middle Aged, Werner Syndrome, Telomere, Cellular Senescence, In Situ Hybridization, Fluorescence, Microscopy, Confocal, Genomic Instability, DNA Repair Enzymes, Intracellular Signaling Peptides and Proteins, DNA Breaks, Double-Stranded
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