Year: 2022
Type: article
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.
Source: Nature Communications
Institutions: The Wistar Institute, Cornell University, Weill Cornell Medicine
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,890
Awards: G1390870092, G1410119253, G1634253349, G193107852, G2456204322, G3946933419, G4331190958, G546097474, G5520316217, G567678477, Integrative Approach to Comprehensive Analysis of High Throughput Data on a Cancer Center Level, G628394963, G6393768786, G69874486, Epigenomic Control of KSHV Latency, Role of TERRA in Telomere Maintenance and Telomere Stress Response, G9000091540, G9000236645, G9000250511, G9000251175, G9000307965, Epigenetic Regulation of Epstein-Barr Virus, Consolidated Basic Cancer Research Program
OpenAlex ID: W4293680959