Phosphorylation of H2A.XTyr39 positively regulates DNA damage response and is linked to cancer progression

Double‐stranded DNA breaks induce serine phosphorylation of histone H2A.X, producing γ‐H2A.X foci that are then recognized by DNA damage response pathway proteins. Formation of γ‐H2A.X is therefore critical for the repair of DNA double‐stranded breaks and maintenance of genomic stability, and defects in the recognition or repair of double‐stranded breaks can result in tumorigenesis. However, key details regarding the formation of γ‐H2A.X and its possible role in tumorigenesis remain elusive. Here, we report a previously unknown phosphorylation site on H2A.X, Tyr39. Phosphorylation at this site is induced by ionizing radiation and is a prerequisite for γ‐H2A.X formation. Increased phosphorylation of H2A.X at Tyr39 was observed in multiple cancer cell lines, and we found that H2AX Tyr39 phosphorylation positively correlated with histological grade, tumor size and tumor node metastasis stage, and negatively correlated with survival. We also identified a potential role for eyes absent 2 (EYA2) in regulating H2A.X Tyr39 phosphorylation. Our study supports an important role for H2AX Tyr39 phosphorylation in γ‐H2A.X formation and cancer progression. Phosphorylation of serine residues of histone H2A.X occurs after DNA double‐strand breaks, producing γ‐H2A.X foci that are recognised by DNA repair enzymes. Defects in γ‐H2A.X formation or recognition can lead to chromosome instability and tumorigenesis. Phosphorylation of tyrosine residues of H2A.X have also been reported, but their role is less clear. Zhang et al. now show that phosphorylation of Tyr 39 of H2A.X functions as a prerequisite for γ‐H2A.X formation. The authors measured high levels of phosphorylated Tyr 39 in multiple human cancer cell lines and these levels correlated positively with tumour size and negatively with survival rates. The authors also showed that Eye Absent 2 (EYA2) dephosphorylates H2A.X Tyr 39 and its activity correlates with cancer progression. This study highlights the role of H2A.X Tyr phosphorylation in potentiating γ‐H2A.X foci formation and tumorigenesis.