title: 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.
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tutton
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Greggory A
authors.initials: GA
authors.lastname: Azzam
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stong
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Vladimirova
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wiedmer
authors.affiliation: Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Monteith
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Beishline
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Deng
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Harold
authors.initials: H
authors.lastname: Riethman
authors.affiliation: Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Murphy
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA Lieberman@wistar.org.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Lieberman
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D011485:Protein Binding; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53
keywords: DNA damage; TERRA; TP53; chromatin; telomere; tumor suppressor