Jul 7, 2007

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

Carcinogenesis
Sheela Hanasoge, Mats Ljungman

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 replicat...Continue Reading

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Mentioned in this Paper

Flow Cytometry
H2AFX gene
DNA Repair Inhibition
Histone antigen
H2AFX wt Allele
Cell Cycle Proteins
DNA Repair
Base Excision Repair
Protein Phosphorylation
Immunocytochemistry

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