DAXX-ATRX regulation of p53 chromatin binding and DNA damage response

Nitish Gulve, Chenhe Su, Zhong Deng, Samantha S. Soldan, Olga Vladimirova, Jayamanna Wickramasinghe, Hongwu Zheng, Andrew V. Kossenkov and Paul. M. Lieberman ()
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Nitish Gulve: The Wistar Institute
Chenhe Su: The Wistar Institute
Zhong Deng: The Wistar Institute
Samantha S. Soldan: The Wistar Institute
Olga Vladimirova: The Wistar Institute
Jayamanna Wickramasinghe: The Wistar Institute
Hongwu Zheng: Cornell University
Andrew V. Kossenkov: The Wistar Institute
Paul. M. Lieberman: The Wistar Institute

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32680-8

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