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.

Department of Genome Dynamics Institute of Molecular Genetics of the Czech Academy of Sciences 142 20 Prague 4 Czech Republic

Department of Radiation Genetics Graduate School of Medicine Kyoto University Yoshidakonoe Sakyo ku Kyoto 606 8501 Japan

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

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

Genome Damage and Stability Centre School of Life Sciences University of Sussex Falmer Brighton BN1 9RQ UK

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

Institute for Cancer Genetics Department of Pathology and Cell Biology College of Physicians and Surgeons Columbia University New York City NY 10032 USA

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

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Early recruitment of PARP-dependent m8A RNA methylation at DNA lesions is subsequently accompanied by active DNA demethylation

XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair