Carcinogenesis Advance Access published online on July 5, 2007
Carcinogenesis, 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, Ann Arbor, MI 48109-2200 and Program in Toxicology, Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109
* To whom correspondence should be addressed: Mats Ljungman, Department of Radiation Oncology, University of Michigan Medical School, 2069 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. Tel: +1 734 764 3330; Fax: +1 734 647 9654; E-mail: ljungman{at}umich.edu
It has been suggested that phosphorylation of the histone variant H2AX after ultraviolet light (UV) irradiation is triggered by 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 XP-A cells. Using chemical inhibitors of the PI(3)-like-kinase family of protein kinases as well as ATR-deficient Seckel syndrome cells and ATM-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.
Received April 11, 2007; revised June 28, 2007; accepted June 29, 2007.
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