2. Academic Validation
  3. XRCC1 prevents toxic PARP1 trapping during DNA base excision repair

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

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: stakeda@rg.med.kyoto-u.ac.jp.
  • 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: k.w.caldecott@sussex.ac.uk.
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.

Figures