Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 27, Issue 12, Pages 1152-U163Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41594-020-0512-7
Keywords
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Funding
- Comprehensive Cancer Center Support Grant NCI [P30CA047904]
- NCI [5R01CA207209-02]
- American Cancer Society [RSG-18-038-01-DMC]
- NIH [1S10OD019973-O1, U24CA210967, R01 GM094231, R01CA148629]
- NIEHS [R01ES014811]
- T32 training grant, NIGMS [T32GM008424-25]
- Cancer Research UK [C480/A11411, C5759/A17098]
- [ERC-2015-ADG- 694694]
- [ANR-16-CE15-0018]
- [ANR-16-CE11-0028]
- [ANR-16-CE12-0024]
- [ITN-765966]
- [ITN-813327]
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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. Proteomic definition of the telomeric PARylome combined with genetic and histone H3.3 deposition assays at telomeres reveals that PAR-regulated HIRA activity compensates for loss of ATRX in ALT cells.
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