Nucleotide excision repair-dependent DNA double-strand break formation and ATM signaling activation in mammalian quiescent cells
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Histone H2A variant H2AX is phosphorylated at Ser(139) in response to DNA double-strand break (DSB) and single-stranded DNA (ssDNA) formation. UV light dominantly induces pyrimidine photodimers, which are removed from the mammalian genome by nucleotide excision repair (NER). We previously reported that in quiescent G0 phase cells, UV induces ATR-mediated H2AX phosphorylation plausibly caused by persistent ssDNA gap intermediates during NER. In this study, we have found that DSB is also generated following UV irradiation in an NER-dependent manner and contributes to an earlier fraction of UV-induced H2AX phosphorylation. The NER-dependent DSB formation activates ATM kinase and triggers the accumulation of its downstream factors, MRE11, NBS1, and MDC1, at UV-damaged sites. Importantly, ATM-deficient cells exhibited enhanced UV sensitivity under quiescent conditions compared with asynchronously growing conditions. Finally, we show that the NER-dependent H2AX phosphorylation is also observed in murine peripheral T lymphocytes, typical nonproliferating quiescent cells in vivo. These results suggest that in vivo quiescent cells may suffer from NER-mediated secondary DNA damage including ssDNA and DSB.
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UVR-induced DNA damage and replication stress also activates ATM, which in turn phosphorylates H2AX.
“Recently, we and others have shown that UVR-induced DNA damage and replication stress also activates ATM [39–42], which in turn phosphorylates H2AX [40;41].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [42]
NER-dependent DSBs in quiescent G0 cells activate ATM kinase and trigger H2AX phosphorylation upon UVR exposure.
“Indeed, recent studies by Wakasugi et. al. showed that NER-dependent DSBs in quiescent G0 cells activate ATM kinase and trigger H2AX phosphorylation upon UVR exposure [64].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [64]
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- Authors
- Wakasugi, M., Sasaki, T., Matsumoto, M., Nagaoka, M., Inoue, K., Inobe, M., Horibata, K., Tanaka, K., & Matsunaga, T.
- Affiliations
- Kanazawa University (JP)
- The University of Osaka (JP)
- Corresponding author
- Matsunaga, Tsukasa
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 289
- Issue
- 41
- Pages
- 28730-28737
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4192521
- OpenAlex
- W2087293292
- Cited by
- 48
- References
- 40
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2022: 5 · 2021: 3 · 2020: 8 · 2019: 3 · 2018: 8 · 2017: 4 · 2016: 7 · 2015: 2
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (25640089, 22131009, 24510068, 26870867, 25281017)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- nucleotide excision repair, DNA double-strand break formation, ATM signaling, H2AX phosphorylation, UV-induced DNA damage, quiescent cells, G0 phase, ATR, MRE11, NBS1, MDC1, UV sensitivity, T cells, single-stranded DNA
- MeSH terms
- MRE11 Homologue Protein, Animals, Cell Line, Transformed, DNA Repair, DNA-Binding Proteins, DNA, Single-Stranded, Fibroblasts, Gene Expression Regulation, Histones, Humans, Nuclear Proteins, Phosphorylation, T-Lymphocytes, Ultraviolet Rays, Signal Transduction, Trans-Activators, Resting Phase, Cell Cycle, Cell Cycle Proteins, Adaptor Proteins, Signal Transducing, Mice, DNA Breaks, Double-Stranded, Primary Cell Culture, Ataxia Telangiectasia Mutated Proteins
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