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. Synopsis Binding of p53 to non-canonical response elements in human subtelomeres confers enhancer-like activities and correlates with increased telomere stability. Non-canonical p53 binding sites were identified in the subtelomeres of both human and mouse. Subtelomeric p53 response elements confer transcription activation in vitro and p53-dependent induction of TERRA, eRNA-like transcripts, and more distal subtelomeric genes. p53 status correlates with enhanced telomere stability and survival in response to etoposide-induced DNA damage. Stress-induced p53 binding to the subtelomere correlates with increased histone acetylation and decreased γH2AX. CRISPR deletion of the p53 response element ameliorates these effects. Binding of p53 to non-canonical response elements in human subtelomeres confers enhancer-like activities and correlates with increased telomere stability.
- DNA damage
- tumor suppressor
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)