Title | DAXX-ATRX regulation of p53 chromatin binding and DNA damage response. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Gulve N, Su C, Deng Z, Soldan SS, Vladimirova O, Wickramasinghe J, Zheng H, Kossenkov AV, Lieberman PM |
Journal | Nat Commun |
Volume | 13 |
Issue | 1 |
Pagination | 5033 |
Date Published | 2022 Aug 26 |
ISSN | 2041-1723 |
Keywords | Chromatin, Co-Repressor Proteins, DNA Damage, DNA Helicases, Genes, Tumor Suppressor, Histones, Molecular Chaperones, Nuclear Proteins, Tumor Suppressor Protein p53, X-linked Nuclear Protein |
Abstract | DAXX and ATRX are tumor suppressor proteins that form a histone H3.3 chaperone complex and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT). Here, we show that DAXX and ATRX knock-out (KO) U87-T cells that have acquired ALT-like features have defects in p53 chromatin binding and DNA damage response. RNA-seq analysis revealed that p53 pathway is among the most perturbed. ChIP-seq and ATAC-seq revealed a genome-wide reduction in p53 DNA-binding and corresponding loss of chromatin accessibility at many p53 response elements across the genome. Both DAXX and ATRX null cells showed a depletion of histone H3.3 and accumulation of γH2AX at many p53 sites, including subtelomeres. These findings indicate that loss of DAXX or ATRX can compromise p53 chromatin binding and p53 DNA damage response in ALT-like cells, providing a link between histone composition, chromatin accessibility and tumor suppressor function of p53. |
DOI | 10.1038/s41467-022-32680-8 |
Alternate Journal | Nat Commun |
PubMed ID | 36028493 |
PubMed Central ID | PMC9418176 |
Grant List | R01 DE017336 / DE / NIDCR NIH HHS / United States P30 CA010815 / CA / NCI NIH HHS / United States R50 CA211199 / CA / NCI NIH HHS / United States R01 CA140652 / CA / NCI NIH HHS / United States R01 CA117830 / CA / NCI NIH HHS / United States |
Related Faculty:
Hongwu Zheng, Ph.D.