Regulation of ALT-associated homology-directed repair by polyADP-ribosylation
Authors
Hoang, S. M.Kaminski, N.
Bhargava, R.
Barroso-González, J.
Lynskey, M. L.
García-Expósito, 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.
Mellacharevu, D.
Nesvizhskii, A. I.
Li, J.
Ray-Gallet, D.
Sobol, R. W.
Almouzni, G.
O'Sullivan, R. J.
Affiliation
Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.Issue Date
2020
Metadata
Show full item recordAbstract
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.Citation
Hoang 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.Journal
Nature Structural and Molecular BiologyDOI
10.1038/s41594-020-0512-7PubMed ID
33046907Additional Links
https://dx.doi.org/10.1038/s41594-020-0512-7Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1038/s41594-020-0512-7
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