p14ARF interacts with γ-H2AX and is involved in the DNA damage response.

p14ARF(ARF) is a tumor suppressor and functionally related to p53. Emerging evidences suggest that ARF triggers DNA damage in a p53-independent manner. However, it remains to be determined how ARF is involved in DNA damage response. Here, we report that ARF is critical in regulating the formation of DNA damage induced γ-H2AX foci. ARF binds to H2AX through its N-terminal domains to promote the phosphorylation of H2AX. The localization of ARF to the site of DNA breaks facilitates the formation of γ-H2AX foci in response to DNA damage. The knocking down of ARF significantly reduced γ-H2AX production and the number of γ-H2AX foci, leading to increased sensitivity to doxorubicin-induced cell death. Together, we propose that ARF plays a crucial role in DNA damage response through its association with H2AX and regulating γ-H2AX formation.