Regulation of ALT-associated homology-directed repair by polyADP-ribosylation
AuthorsHoang, S. M.
Lynskey, M. L.
Roncaioli, J. L.
Wondisford, A. R.
Wallace, C. T.
Watkins, S. C.
James, Dominic I
Waddell, Ian D
Ogilvie, Donald J
Smith, Kate M
da Veiga Leprevost, F.
Nesvizhskii, A. I.
Sobol, R. W.
O'Sullivan, R. J.
AffiliationDepartment of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
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AbstractThe 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.
CitationHoang SM, Kaminski N, Bhargava R, Barroso-Gonzalez J, Lynskey ML, Garcia-Exposito L, et al. Regulation of ALT-associated homology-directed repair by polyADP-ribosylation. Nat Struct Mol Biol. 2020.
JournalNature Structural and Molecular Biology
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