Histone H2A.X is a histone variant found in almost all eukaryotes that plays a crucial role in maintaining genome stability. It is highly conserved across species and has a unique C-terminal tail containing an SQ motif, which is phosphorylated by kinases like ATM and ATR in response to DNA double-strand breaks (DSBs) to form 纬-H2A.X. This phosphorylation event is a very early and highly conserved response to DNA damage, occurring within minutes in mammals and extending over large chromatin regions around the damage site. 纬-H2A.X acts as a major signal to recruit DNA repair factors to the damaged site, facilitating efficient repair and preserving genomic integrity. Deficiencies in H2A.X or its phosphorylation can lead to genomic instability, increased sensitivity to DNA-damaging agents, and a higher risk of tumor formation. Additionally, H2A.X is involved in various other cellular processes, including the regulation of gene expression, immune response, and the establishment of cell fate.