Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres

Stephen Tutton, Greggory A. Azzam, Nicholas Stong, Olga Vladimirova, Andreas Wiedmer, Jessica A. Monteith, Kate Beishline, Zhuo Wang, Zhong Deng, Harold Riethman, Steven B. McMahon, Maureen Murphy, Paul M. Lieberman

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)193-207
Number of pages15
JournalEMBO Journal
Volume35
Issue number2
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Keywords

  • chromatin
  • DNA damage
  • telomere
  • TERRA
  • TP53
  • tumor suppressor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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