Homologous recombination-dependent repair of telomeric DSBs in proliferating human cells
Open accessAbstract
Telomeres prevent chromosome ends from being recognized as double-stranded breaks (DSBs). Meanwhile, G/C-rich repetitive telomeric DNA is susceptible to attack by DNA-damaging agents. How cells balance the need to protect DNA ends and the need to repair DNA lesions in telomeres is unknown. Here we show that telomeric DSBs are efficiently repaired in proliferating cells, but are irreparable in stress-induced and replicatively senescent cells. Using the CRISPR-Cas9 technique, we specifically induce DSBs at telomeric or subtelomeric regions. We find that DSB repair (DSBR) at subtelomeres occurs in an error-prone manner resulting in small deletions, suggestive of NHEJ. However, DSBR in telomeres involves ‘telomere-clustering’, 3′-protruding C-rich telomeric ssDNA, and HR between sister-chromatid or interchromosomal telomeres. DSBR in telomeres is suppressed by deletion or inhibition of Rad51. These findings reveal proliferation-dependent DSBR in telomeres and suggest that telomeric HR, which is normally constitutively suppressed, is activated in the context of DSBR.
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Homologous recombination repair is restricted to proliferating cells undergoing S-phase and is therefore unlikely to be relevant for post-mitotic cardiomyocytes.
“In contrast, homologous recombination can repair telomere‐induced DNA damage; however, this process is restricted to proliferating cells undergoing S‐phase and therefore not likely to be relevant for post‐mitotic CMs (Mao et al, 2016).”
From Length-independent telomere damage drives post-mitotic cardiomyocyte senescence (2019) · cites this paper as Mao et al, 2016
The Abstract reports homologous recombination-dependent repair of telomeric breaks in proliferating human cells, but not in senescent cells. The Discussion (page unavailable) treats the timing of that repair within the cell cycle as an open question, rather than establishing that it is restricted to S-phase. The paper does not study post-mitotic cardiomyocytes, so the proposed implication for them is not directly supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHomologous recombination can repair telomere-induced DNA damage.
“In contrast, homologous recombination can repair telomere‐induced DNA damage; however, this process is restricted to proliferating cells undergoing S‐phase and therefore not likely to be relevant for post‐mitotic CMs (Mao et al, 2016).”
From Length-independent telomere damage drives post-mitotic cardiomyocyte senescence (2019) · cites this paper as Mao et al, 2016
The Abstract reports that telomeric double-strand breaks are repaired in proliferating human cells and that multiple features point to homologous recombination. But the Discussion explicitly leaves open whether this repair occurs only in late S and G2, so the cited paper does not establish the sentence’s S-phase restriction or test its relevance to post-mitotic cardiomyocytes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredProliferation rate is an important determinant of telomeric DSB repair.
“suggesting that proliferation rate is an important determinant of telomeric DSB repair (Mao et al., 2016).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Mao et al., 2016
Repair at telomeres is only observed in proliferating cells, such as BJ fibroblasts and HeLa cells.
“repair at telomeres was only observed in proliferating cells, such as BJ fibroblasts and HeLa cells.”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Mao et al., 2016
DSB repair can occur at telomeres.
“studies which have provided evidence that DSB repair can occur at telomeres (Doksani and de Lange, 2016, Mao et al., 2016).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Mao et al., 2016
HeLa cells display faster repair kinetics compared to slower dividing fibroblasts.
“HeLa cells, which are faster dividing cells, display a faster repair kinetics compared to slower dividing fibroblasts”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Mao et al., 2016
Generating telomeric DSBs did not lead to senescence in both cases.
“it was reported that generating telomeric DSBs did not lead to senescence in both cases”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Mao et al., 2016
When senescence is induced in fibroblasts by genotoxic stress or replicative exhaustion, no significant repair at chromosome ends is detected.
“when senescence was induced in fibroblasts either by genotoxic stress or replicative exhaustion, both of which were associated with increased telomeric DDR signaling, no significant repair at chromosome ends was detected (Mao et al., 2016).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Mao et al., 2016
The cells used in the telomeric DSB studies are immortalized.
“the cells used in these studies are immortalized (Doksani and de Lange, 2016, Mao et al., 2016).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Mao et al., 2016
Homologous recombination plays an important role in telomere damage repair.
“demonstrated that homologous recombination (HR) plays an important role in telomere damage repair (Mao et al., 2016).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Mao et al., 2016
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- Authors
- Mao, P., Liu, J., Zhang, Z., Zhang, H., Liu, H., Gao, S., Rong, Y. S., & Zhao, Y.
- Affiliations
- Sun Yat-sen University (CN)
- Corresponding author
- Zhao, Yong
- Venue
- Nature Communications
- Published
- 2016-07-11
- Volume
- 7
- Issue
- 1
- Pages
- 12154-12154
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4942568
- OpenAlex
- W2464486432
- Cited by
- 76
- References
- 65
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 9 · 2021: 10 · 2020: 5 · 2019: 12 · 2018: 9 · 2017: 6
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (2014CB964703, 31271472, 31322033, 31301110)
- National Key Research and Development Program of China (2014CB964703)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- telomeres, DNA double-strand break repair, homologous recombination, telomeric DNA damage, subtelomeric regions, non-homologous end joining, RAD51, replicative senescence, stress-induced senescence, sister chromatid recombination, single-stranded DNA, error-prone repair, proliferating cells
- MeSH terms
- Fibroblasts, HeLa Cells, Humans, Telomere, Cellular Senescence, Cell Proliferation, HEK293 Cells, DNA End-Joining Repair, Recombinational DNA Repair, CRISPR-Cas Systems
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