Critical role of lysine 134 methylation on histone H2AX for gamma-H2AX production and DNA repair

The presence of phosphorylated histone H2AX (g-H2AX) is associated with the local activation of DNA-damage repair pathways. Although g-H2AX deregulation in cancer has previously been reported, the molecular mechanism involved and its relationship with other histone modifications remain largely unknown. Here we find that the histone methyl-transferase SUV39H2 methylates histone H2AX on lysine 134. When H2AX was mutated to abolish K134 methylation, the level of g-H2AX became significantly reduced. We also found lower g-H2AX activity following the introduction of double-strand breaks in Suv39h2 knockout cells or on SUV39H2 knockdown. Tissue microarray analyses of clinical lung and bladder tissues also revealed a positive correlation between H2AX K134 methylation and g-H2AX levels. Furthermore, introduction of K134-substituted histone H2AX enhanced radio- and chemosensitivity of cancer cells. Overall, our results suggest that H2AX methylation plays a role in the regulation of g-H2AX abundance in cancer