Title: Regulation of ALT-associated homology-directed repair by polyADP-ribosylation.
Authors: Hoang, Song My; Kaminski, Nicole; Bhargava, Ragini; Barroso-González, Jonathan; Lynskey, Michelle L; García-Expósito, Laura; Roncaioli, Justin L; Wondisford, Anne R; Wallace, Callen T; Watkins, Simon C; James, Dominic I; Waddell, Ian D; Ogilvie, Donald; Smith, Kate M; da Veiga Leprevost, Felipe; Mellacharevu, Dattatreya; Nesvizhskii, Alexey I; Li, Jianfeng; Ray-Gallet, Dominique; Sobol, Robert W; Almouzni, Genevieve; O'Sullivan, Roderick J
Published In Nat Struct Mol Biol, (2020 12)
Abstract: 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.
PubMed ID: 33046907
MeSH Terms: Cell Cycle Proteins/antagonists & inhibitors; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Cell Line, Tumor; Chromatin/metabolism; Chromatin/ultrastructure; DNA Damage; DNA, Neoplasm/genetics*; DNA, Neoplasm/metabolism; Epithelial Cells/metabolism; Epithelial Cells/pathology; G2 Phase; Gene Expression Regulation, Neoplastic*; Glycoside Hydrolases/genetics*; Glycoside Hydrolases/metabolism; HeLa Cells; Histone Chaperones/antagonists & inhibitors; Histone Chaperones/genetics; Histone Chaperones/metabolism; Histones/genetics; Histones/metabolism; Humans; Poly ADP Ribosylation; Poly Adenosine Diphosphate Ribose/metabolism; Poly(ADP-ribose) Polymerases/genetics*; Poly(ADP-ribose) Polymerases/metabolism; Protein Processing, Post-Translational*; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Recombinational DNA Repair*; Signal Transduction; Telomere Homeostasis; Telomere/metabolism*; Telomere/ultrastructure; Transcription Factors/antagonists & inhibitors; Transcription Factors/genetics; Transcription Factors/metabolism; X-linked Nuclear Protein/genetics; X-linked Nuclear Protein/metabolism