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

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 γH2AX. 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 γH2AX expression can be used to detect the genotoxic effect of different toxic substances. When applied to clinical samples from cancer patients, evaluation of γH2AX 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.

Identification and Characterization of New Chemical Entities Targeting Apurinic/Apyrimidinic Endonuclease 1 for the Prevention of Chemotherapy-Induced Peripheral Neuropathy

“…As further confirmation of the neuroprotective effects of APX2009 after cisplatin treatment, the levels of pH2AX, a marker of DNA damage (Podhorecka et al, 2010;Redon et al, 2010;Crowe et al, 2011), were measured in sensory neuronal cultures in the absence or presence of various E3330 analogs. When cultures were exposed to 10 mM cisplatin for 24 or 48 hours, there is a significant increase in the levels of pH2AX as measured using Western blotting confirming DNA damage by the platinum compound (Fig.…”

Identification and Characterization of an Oocyte Factor Required for Porcine Nuclear Reprogramming

“…Because DSBs induce DNA damage response (53,54) and the DNA damage response activates the p53 pathway (37), p53 activation in the VIM-deficient cloned embryos might be a result of DSBs. p53 responds to various cellular stresses and induces cell cycle arrest, DNA repair, and cell apoptosis (55)(56)(57) and finally affects embryo viability (58).…”

Overt Increase of Oxidative Stress and DNA Damage in Murine and Human Colitis and Colitis-Associated Neoplasia

“…(13,14) An early event in DSB response is phosphorylation of the H2A subtype histone H2AX at ser-139 (also known as γH2AX) by the phosphatidylinositol 3-like kinases ATM, ATR and DNA-PK. (15,16) Phosphorylation of H2AX spreads from the site of a DSB into both directions, resulting in initiation and maintenance of DDR. Hence, γH2AX is a recruits several DDR proteins at DSBs and activates DNA repair either by homologous recombination (HR) or non-homologous end joining (NHEJ) (19).…”