H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase
Abstract
It has been suggested that phosphorylation of the histone variant H2AX after ultraviolet light (UV) irradiation is triggered by DNA double-strand breaks induced as replication forks collide with UV-induced bulky lesions. More recently, it has been shown that UV-induced H2AX phosphorylation can also occur outside of S-phase, but the mechanism for this replication-independent induction is not well understood. In this study, we show that H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is induced in all phases of the cell cycle. Accumulation of DNA repair intermediates by inhibition of DNA repair synthesis resulted in a marked increase of H2AX phosphorylation in repair proficient but not repair-deficient xeroderma pigmentosum-A cells. Using chemical inhibitors of the PI(3)-like kinase family of protein kinases as well as ataxia telangiectasia mutated and Rad-3 related (ATR)-deficient Seckel syndrome cells and ataxia telangiectasia mutated-deficient ataxia telangiectasia cells, we show that the H2AX phosphorylation induced by accumulation of repair intermediates is mediated primarily by the ATR kinase. We suggest a model for UV light-induced phosphorylation of H2AX where in addition to replication blockage, DNA repair intermediates trigger H2AX phosphorylation via the ATR kinase.
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Several studies have reported that NER factor-mediated lesion processing might be required for γH2AX foci formation.
“However, several studies reported that lesion processing by NER factors might be an essential step in γH2AX foci formation [35-39].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [37]
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- Authors
- Hanasoge, S., & Ljungman, M.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Ljungman, M.
- ORCID
- Ljungman, M.
- Venue
- Carcinogenesis
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-09-07
- Volume
- 28
- Issue
- 11
- Pages
- 2298-2304
- ISSN
- 0143-3334 (ISSN-L)
- 1460-2180
- OpenAlex
- W2140549234
- Cited by
- 216
- References
- 44
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 13 · 2023: 6 · 2022: 11 · 2021: 11 · 2020: 5 · 2019: 15 · 2018: 10 · 2017: 6 · 2016: 12 · 2015: 5 · 2014: 19 · 2013: 12 · 2012: 11
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (5P30 CA 46592, P30CA046592)
- 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 › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- H2AX phosphorylation, UV irradiation, ATR kinase, DNA repair intermediates, DNA double-strand breaks, PI3K inhibitors, ataxia telangiectasia, replication fork stalling, cell cycle, histone variants
- MeSH terms
- Cell Cycle, DNA Repair, Dose-Response Relationship, Radiation, Flow Cytometry, Histones, Humans, Immunohistochemistry, Phosphorylation, Ultraviolet Rays, Blotting, Western, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins
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