Open AccessRegulation of ALT-associated homology-directed repair by polyADP-ribosylation
Author(s) -
Song My Hoang,
Nicole Kaminski,
Ragini Bhargava,
Jonathan Barroso-González,
Michelle Lee Lynskey,
Laura García-Expósito,
Justin L. Roncaioli,
Anne R. Wondisford,
Callen T. Wallace,
Simon C. Watkins,
Dominic I. James,
Ian D. Waddell,
Donald Ogilvie,
Kate Smith,
Felipe da Veiga Leprevost,
Dattatreya Mellacharevu,
Alexey I. Nesvizhskii,
Jianfeng Li,
Dominique Ray-Gallet,
Robert W. Sobol,
Geneviève Almouzni,
Roderick J. O’Sullivan
Publication year - 2020
Publication title -
nature structural and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.448
H-Index - 270
eISSN - 1545-9993
pISSN - 1545-9985
DOI - 10.1038/s41594-020-0512-7
Subject(s) - atrx , telomere , chromatin , histone , dna repair , biology , microbiology and biotechnology , dna damage , poly adp ribose polymerase , dna , genome instability , cancer research , genetics , mutation , gene , polymerase
The synthesis of poly(ADP-ribose) (PAR) reconfigures the local chromatin environment and recruits DNA-repair complexes to damaged chromatin. PAR degradation by poly(ADP-ribose) glycohydrolase (PARG) is essential for progression and completion of DNA repair. Here, we show that inhibition of PARG disrupts homology-directed repair (HDR) mechanisms that underpin alternative lengthening of telomeres (ALT). Proteomic analyses uncover a new role for poly(ADP-ribosyl)ation (PARylation) in regulating the chromatin-assembly factor HIRA in ALT cancer cells. We show that HIRA is enriched at telomeres during the G2 phase and is required for histone H3.3 deposition and telomere DNA synthesis. Depletion of HIRA elicits systemic death of ALT cancer cells that is mitigated by re-expression of ATRX, a protein that is frequently inactivated in ALT tumors. We propose that PARylation enables HIRA to fulfill its essential role in the adaptive response to ATRX deficiency that pervades ALT cancers.