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We revealed that FA also damages DNA bases adjoining the DPCs, leading to DPC-conjugated 5\u2032 flap structures via the base excision repair (BER) pathway. We also found that FEN1 repairs enzymatic topoisomerase II (TOP2)\u2013DPCs. Furthermore, we report that both FA-induced and TOP2-DPCs are adenosine diphosphate (ADP) ribosylated by poly(ADP-ribose) polymerase 1 (PARP1). PARylation of the DPCs in association with FEN1 PARylation at residue E285 is required for the recruitment of FEN1. Our work unveils the identity of proteins forming FA-induced DPCs and a previously unrecognized PARP1-FEN1 nuclease pathway repairing both FA- and TOP2-DPCs.<\/jats:p>","DOI":"10.1126\/sciadv.ads2919","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T13:58:24Z","timestamp":1736517504000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":14,"title":["Flap endonuclease 1 repairs DNA-protein cross-links via ADP-ribosylation\u2013dependent mechanisms"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6249-2704","authenticated-orcid":true,"given":"Yilun","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Physiology and Drug Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA."},{"name":"University of Maryland Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, Baltimore, MD 21201, 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