H2AX Phosphorylation: Its Role in DNA Damage Response and Cancer Therapy - PubMed (original) (raw)

H2AX Phosphorylation: Its Role in DNA Damage Response and Cancer Therapy

Monika Podhorecka et al. J Nucleic Acids. 2010.

Abstract

Double-strand breaks (DSBs) are the most deleterious DNA lesions, which, if left unrepaired, may have severe consequences for cell survival, as they lead to chromosome aberrations, genomic instability, or cell death. Various physical, chemical, and biological factors are involved in DSB induction. Cells respond to DNA damage by activating the so-called DNA damage response (DDR), a complex molecular mechanism developed to detect and repair DNA damage. The formation of DSBs triggers activation of many factors, including phosphorylation of the histone variant H2AX, producing gammaH2AX. Phosphorylation of H2AX plays a key role in DDR and is required for the assembly of DNA repair proteins at the sites containing damaged chromatin as well as for activation of checkpoints proteins which arrest the cell cycle progression. In general, analysis of gammaH2AX expression can be used to detect the genotoxic effect of different toxic substances. When applied to clinical samples from cancer patients, evaluation of gammaH2AX levels may allow not only to monitor the efficiency of anticancer treatment but also to predict of tumor cell sensitivity to DNA damaging anticancer agents and toxicity of anticancer treatment toward normal cells.

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Figure 1

Figure 1

H2AX phosphorylation and its role in DNA damage response upon phosphorylation H2AX became critical player in DNA damage response. Activity of _γ_H2AX could be summarized to following main points: accumulation of DNA damage signaling and repair proteins at DSBs The generation of DSBs triggers the relocalization of many DNA damage response (DDR) proteins such as MRE11/NBS1/RAD50, MDC1, 53BP1and BRCA1 to nuclear foci where these proteins colocalize and interact with _γ_H2AX. Signal amplification and induction of DNA damage-sensitive cell cycle checkpoints _γ_H2AX contribute to the recruitment of ATM to DSB sites and activation of ATM-dependent cell cycle checkpoints. Chromatin remodeling to prevent dissociation of break ends and enhance DSB processing and repair efficiency The _γ_H2AX foci help keeping the broken DNA ends together and make successful and faithful repair more likely. Recruitment of cohesins to the site of DNA damage to promote sister chromatid-dependent recombinational repair DNA cohesion induced by double-strand DNA break and mediated by _γ_H2AX has an important function during repair of double-strand breaks following DNA replication by holding the damaged chromatid close to its undamaged sister template.

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