HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia.

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia.

Biol Chem. 2012 Dec 14;

Authors: Wrann S, Kaufmann MR, Wirthner R, Stiehl DP, Wenger RH

Abstract
Abstract The histone variant 2AX (H2AX) is phosphorylated at Ser139 by the PI3K-like kinase family members ATM, ATR and DNA-PK. Genotoxic stress such as tumor radio- and chemotherapy is considered to be the main inducer of phosphorylated H2AX (?H2AX) which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. ?H2AX accumulation under severe hypoxic/anoxic (0.02% oxygen) conditions has recently been reported to follow replication fork stalling in the absence of detectable DNA damage. In this study, we found HIF dependent accumulation of ?H2AX in several cancer cell lines and mouse embryonic fibroblasts exposed to physiologically relevant chronic hypoxia (0.2% oxygen) which did not induce detectable levels of DNA strand breaks. The hypoxic accumulation of ?H2AX was delayed by RNAi mediated knockdown of HIF-1? or HIF-2? and further decreased when both HIF-?s were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2?. These results suggest that both HIF-1 and HIF-2 are involved in ?H2AX accumulation by tumor hypoxia which might increase the cancer cell's capacity to repair DNA damage, contributing to tumor therapy resistance.

PMID: 23241668 [PubMed - as supplied by publisher]

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