XRCC1 prevents toxic PARP1 trapping during DNA base excision repair

Demin, Annie A, Hirota, Kouji, Tsuda, Masataka, Adamowicz, Marek, Hailstone, Richard, Brazina, Jan, Gittens, William, Kalasova, Ilona, Shao, Zhengping, Zha, Shan, Sasanuma, Hiroyuki, Hanzlikova, Hana, Takeda, Shunichi and Caldecott, Keith W (2021) XRCC1 prevents toxic PARP1 trapping during DNA base excision repair. Molecular Cell, 81 (14). 3018-3030.e5. ISSN 1097-2765

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Abstract

Mammalian 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 β 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 β 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.

Item Type: Article
Keywords: PARP inhibitors, PARP trapping, PARP1, XRCC1 protein complexes, base excision repair, single-strand breaks, Animals, Cell Line, DNA, DNA Breaks, Single-Stranded, DNA Damage, DNA Ligase ATP, DNA Polymerase beta, DNA Repair, DNA-Binding Proteins, Fibroblasts, Humans, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Protein Binding, X-ray Repair Cross Complementing Protein 1
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 27 Sep 2021 15:51
Last Modified: 27 Sep 2021 16:00
URI: http://sro.sussex.ac.uk/id/eprint/101947

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