Regulation of ALT-associated homology-directed repair by polyADP-ribosylation
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.
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.
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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.
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.
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.
Description
Date
2020
Publisher
Collections
Keywords
Type
Article
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.