Cited by 216DNA Repair MechanismsEffects of Radiation ExposureCarcinogens and Genotoxicity Assessment

H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase

Hanasoge, S., Ljungman, M.·2007·Carcinogenesis

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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Crossref · 10.1093/carcin/bgm157

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Authors
Hanasoge, S., & Ljungman, M.
Affiliations
University of Michigan (US)
Corresponding author
Ljungman, M.
Venue
Carcinogenesis
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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