HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia
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Simon Wrann
Abstract
The histone variant 2AX (H2AX) is phosphorylated at Serine 139 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 the 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 a cancer cell’s capacity to repair DNA damage, contributing to tumor therapy resistance.
©2013 by Walter de Gruyter Berlin Boston
Articles in the same Issue
- Masthead
- Masthead
- Guest Editorial
- Highlight: sensing hypoxia in the cell and the organism
- Highlight: Sensing Hypoxia in the Cell and the Organism
- Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles
- The regulation, localization, and functions of oxygen-sensing prolyl hydroxylase PHD3
- Deciphering the emerging role of SUMO conjugation in the hypoxia-signaling cascade
- Hypoxia, the HIF pathway and neutrophilic inflammatory responses
- Hydroxylase-dependent regulation of the NF-κB pathway
- Role of hypoxia inducible factor-1α for interferon synthesis in mouse dendritic cells
- Pan-genomic binding of hypoxia-inducible transcription factors
- HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia
- Noninvasive assessment of hypoxia with 3-[18F]-fluoro-1-(2-nitro-1-imidazolyl)-2-propanol ([18F]-FMISO): a PET study in two experimental models of human glioma
- Research Articles/Short Communications
- Protein Structure and Function
- Homo- and heterotypic interactions between Pss proteins involved in the exopolysaccharide transport system in Rhizobium leguminosarum bv. trifolii
- Proteolysis
- Combination of quercetin and tannic acid in inhibiting 26S proteasome affects S5a and 20S expression, and accumulation of ubiquitin resulted in apoptosis in cancer chemoprevention
Articles in the same Issue
- Masthead
- Masthead
- Guest Editorial
- Highlight: sensing hypoxia in the cell and the organism
- Highlight: Sensing Hypoxia in the Cell and the Organism
- Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles
- The regulation, localization, and functions of oxygen-sensing prolyl hydroxylase PHD3
- Deciphering the emerging role of SUMO conjugation in the hypoxia-signaling cascade
- Hypoxia, the HIF pathway and neutrophilic inflammatory responses
- Hydroxylase-dependent regulation of the NF-κB pathway
- Role of hypoxia inducible factor-1α for interferon synthesis in mouse dendritic cells
- Pan-genomic binding of hypoxia-inducible transcription factors
- HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia
- Noninvasive assessment of hypoxia with 3-[18F]-fluoro-1-(2-nitro-1-imidazolyl)-2-propanol ([18F]-FMISO): a PET study in two experimental models of human glioma
- Research Articles/Short Communications
- Protein Structure and Function
- Homo- and heterotypic interactions between Pss proteins involved in the exopolysaccharide transport system in Rhizobium leguminosarum bv. trifolii
- Proteolysis
- Combination of quercetin and tannic acid in inhibiting 26S proteasome affects S5a and 20S expression, and accumulation of ubiquitin resulted in apoptosis in cancer chemoprevention
