XRCC1 prevents toxic PARP1 trapping during DNA base excision repair

Mol Cell. 2021 Jul 15;81(14):3018-3030.e5. doi: 10.1016/j.molcel.2021.05.009.

Annie A Demin ¹, Kouji Hirota ², Masataka Tsuda ³, Marek Adamowicz ¹, Richard Hailstone ¹, Jan Brazina ¹, William Gittens ¹, Ilona Kalasova ⁴, Zhengping Shao ⁵, Shan Zha ⁶, Hiroyuki Sasanuma ⁷, Hana Hanzlikova ⁸, Shunichi Takeda ⁹, Keith W Caldecott ¹⁰

Affiliations

1 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
2 Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto 606-8501, Japan; Department of Chemistry, Tokyo Metropolitan University, Minami-Osawa, Hachioji-shi, Tokyo 192-0397, Japan.
3 Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto 606-8501, Japan; Program of Mathematical and Life Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
4 Department of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20 Prague 4, Czech Republic.
5 Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York City, NY 10032, USA.
6 Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York City, NY 10032, USA; Division of Pediatric Oncology, Hematology and Stem Cell Transplantation, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
7 Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto 606-8501, Japan.
8 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK; Department of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20 Prague 4, Czech Republic.
9 Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: [email protected].
10 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK; Department of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20 Prague 4, Czech Republic. Electronic address: [email protected].

PMID: 34102106 DOI: 10.1016/j.molcel.2021.05.009

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.

Keywords

PARP inhibitors; PARP trapping; PARP1; XRCC1 protein complexes; base excision repair; single-strand breaks.

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