H2AX

H2AX is a variant of histone H2A, a core component of nucleosomes that package DNA in eukaryotic chromatin. It is encoded by the H2AFX gene in humans and is expressed broadly in most cell types as part of the histone H2A family.

In response to DNA double-strand breaks, the PI3K-related kinases ATM, ATR, and DNA-PKcs phosphorylate serine 139 of H2AX, producing gamma-H2AX. This modification occurs rapidly and spreads over megabases around the break site, forming nuclear foci that mark damaged chromatin. Gamma-H2AX serves as a recruitment platform for a network of DNA damage response proteins, including MDC1, 53BP1, BRCA1, and the MRN complex, as well as ubiquitin ligases such as RNF8 and RNF168, thereby amplifying the damage signal and orchestrating repair.

Functionally, gamma-H2AX signaling helps stabilize broken DNA ends, facilitates the accumulation of repair factors, and influences pathway choice between homologous recombination and non-homologous end joining. As repair proceeds, gamma-H2AX signals diminish and foci dissolve.

Loss or deficiency of H2AX impairs DNA damage signaling and increases cellular sensitivity to ionizing radiation and other DNA-damaging agents, with greater genomic instability observed in H2AX-deficient models. In research and clinical contexts, gamma-H2AX foci are widely used as a biomarker of DNA double-strand breaks and to monitor DNA repair kinetics via immunofluorescence or related assays.