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XRCC1 prevents toxic PARP1 trapping during DNA base excision repair
journal contribution
posted on 2023-06-10, 01:11 authored by Annie Demin, Kouji Hirota, Masataka Tsuda, Marek Adamowicz, Richard Hailstone, Jan Brazina, William GittensWilliam Gittens, Ilona Kalasova, Zhengping Shao, Shan Zha, Hiroyuki Sasanuma, Hana Hanzlikova, Shunichi Takeda, Keith CaldecottKeith CaldecottMammalian DNA base excision repair (BER) is accelerated by poly(ADP-ribose) polymerases (PARPs) and the scaffold protein XRCC1. PARPs are sensors that detect single-strand break intermediates, but the critical role of XRCC1 during BER is unknown. Here, we show that protein complexes containing DNA polymerase ß and DNA ligase III that are assembled by XRCC1 prevent excessive engagement and activity of PARP1 during BER. As a result, PARP1 becomes “trapped” on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease. This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase ß and impedes their repair. Consequently, PARP1 deletion rescues BER and resistance to base damage in XRCC1-/- cells. These data reveal excessive PARP1 engagement during BER as a threat to genome integrity and identify XRCC1 as an “anti-trapper” that prevents toxic PARP1 activity.
History
Publication status
- Published
File Version
- Published version
Journal
Molecular CellISSN
1097-2765Publisher
Cell PressExternal DOI
Issue
14Volume
81Page range
3018-3030.e5Event location
United StatesDepartment affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-09-27First Open Access (FOA) Date
2021-09-27First Compliant Deposit (FCD) Date
2021-09-27Usage metrics
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No categories selectedKeywords
PARP inhibitorsPARP trappingPARP1XRCC1 protein complexesbase excision repairsingle-strand breaksAnimalsCell LineDNADNA BreaksSingle-StrandedDNA DamageDNA Ligase ATPDNA Polymerase betaDNA RepairDNA-Binding ProteinsFibroblastsHumansPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesProtein BindingX-ray Repair Cross Complementing Protein 1
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