Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres.

Abstract Telomeres and tumor suppressor protein TP53 (p53) function in genome protection, but a direct role of p53 at telomeres has not yet been described. Here, we have identified non‐canonical p53‐binding sites within the human subtelomeres that suppress the accumulation of DNA damage at telomeric repeat DNA. These non‐canonical subtelomeric p53‐binding sites conferred transcription enhancer‐like functions that include an increase in local histone H3K9 and H3K27 acetylation and stimulation of subtelomeric transcripts, including telomere repeat‐containing RNA (TERRA). p53 suppressed formation of telomere‐associated γH2AX and prevented telomere DNA degradation in response to DNA damage stress. Our findings indicate that p53 provides a direct chromatin‐associated protection to human telomeres, as well as other fragile genomic sites. We propose that p53‐associated chromatin modifications enhance local DNA repair or protection to provide a previously unrecognized tumor suppressor function of p53.