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


Wrann, Simon; Kaufmann, Muriel R; Wirthner, Renato; Stiehl, Daniel P; Wenger, Roland H (2013). HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia. Biological Chemistry, 394(4):519-528.

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 (γH2AX) which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. γH2AX 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 γH2AX 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 γH2AX was delayed by RNAi mediated knockdown of HIF-1α or HIF-2α and further decreased when both HIF-αs were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2α. These results suggest that both HIF-1 and HIF-2 are involved in γH2AX accumulation by tumor hypoxia which might increase the cancer cell's capacity to repair DNA damage, contributing to tumor therapy resistance.

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 (γH2AX) which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. γH2AX 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 γH2AX 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 γH2AX was delayed by RNAi mediated knockdown of HIF-1α or HIF-2α and further decreased when both HIF-αs were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2α. These results suggest that both HIF-1 and HIF-2 are involved in γH2AX accumulation by tumor hypoxia which might increase the cancer cell's capacity to repair DNA damage, contributing to tumor therapy resistance.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2013
Deposited On:21 Dec 2012 14:38
Last Modified:05 Apr 2016 16:14
Publisher:Walter de Gruyter
ISSN:1431-6730
Publisher DOI:https://doi.org/10.1515/hsz-2012-0311

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