Carcinogenesis Advance Access originally published online on July 5, 2007
Carcinogenesis 2007 28(11):2298-2304; doi:10.1093/carcin/bgm157
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H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase
1 Department of Radiation Oncology, Division of Radiation and Cancer Biology, University of Michigan Comprehensive Cancer Center
2 Program in Toxicology, Department of Environmental Health Sciences, School of Public Health, University of Michigan, 2069 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
* To whom correspondence should be addressed. Tel: +1 734 764 3330; Fax: +1 734 647 9654; Email: ljungman{at}umich.edu
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.
Abbreviations: araC, cytosine arabinoside; ATR, ataxia telangiectasia mutated and Rad-3 related; ATM, ataxia telangiectasia mutated; CS, Cockayne's syndrome; DSB, double-strand breaks; GGR, global genomic repair; HU, hydroxyurea; MEM, modified Eagle medium; NER, nucleotide excision repair; PBS, phosphate-buffered saline; TCR, transcription-coupled repair; UV, ultraviolet light; UVC, ultraviolet light C; XP, xeroderma pigmentosum
Received April 11, 2007; revised June 28, 2007; accepted June 29, 2007.
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