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.