Regulation of ALT-associated homology-directed repair by polyADP-ribosylation.

Autor: Hoang SM; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., Kaminski N; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., Bhargava R; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., Barroso-González J; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., Lynskey ML; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., García-Expósito L; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., Roncaioli JL; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., Wondisford AR; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., Wallace CT; Department of Cell Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., Watkins SC; Department of Cell Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., James DI; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, Macclesfield, UK., Waddell ID; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, Macclesfield, UK., Ogilvie D; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, Macclesfield, UK., Smith KM; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, Macclesfield, UK., da Veiga Leprevost F; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Mellacharevu D; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Nesvizhskii AI; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA., Li J; Department of Pharmacology and the Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Ray-Gallet D; Institut Curie, PSL Research University, CNRS, Sorbonne Université, Nuclear Dynamics Unit, Equipe Labellisée, Ligue contre le Cancer, Paris, France., Sobol RW; Department of Pharmacology and the Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA., Almouzni G; Institut Curie, PSL Research University, CNRS, Sorbonne Université, Nuclear Dynamics Unit, Equipe Labellisée, Ligue contre le Cancer, Paris, France., O'Sullivan RJ; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. osullivanr@upmc.edu.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2020 Dec; Vol. 27 (12), pp. 1152-1164. Date of Electronic Publication: 2020 Oct 12.
DOI: 10.1038/s41594-020-0512-7
Abstrakt: 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.
Databáze: MEDLINE