{"doi":"10.1126/sciadv.ads2919","title":"Flap endonuclease 1 repairs DNA-protein cross-links via ADP-ribosylation–dependent mechanisms","abstract":"DNA-protein cross-links (DPCs) are among the most detrimental genomic lesions. They are ubiquitously produced by formaldehyde (FA), and failure to repair FA-induced DPCs blocks chromatin-based processes, leading to neurodegeneration and cancer. The type, structure, and repair of FA-induced DPCs remain largely unknown. Here, we profiled the proteome of FA-induced DPCs and found that flap endonuclease 1 (FEN1) resolves FA-induced DPCs. We revealed that FA also damages DNA bases adjoining the DPCs, leading to DPC-conjugated 5' flap structures via the base excision repair (BER) pathway. We also found that FEN1 repairs enzymatic topoisomerase II (TOP2)-DPCs. 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.","journal":"Science Advances","year":2025,"id":516842,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":261931,"name":"Lisa M. Jenkins","orcid":"0000-0003-1245-1338","position":1,"is_corresponding":false},{"id":739294,"name":"Lara H. El Touny","orcid":null,"position":2,"is_corresponding":false},{"id":1382745,"name":"Linying Zhu","orcid":"0000-0002-8181-5126","position":3,"is_corresponding":false},{"id":855932,"name":"Xi Yang","orcid":"0000-0003-0689-1417","position":4,"is_corresponding":false},{"id":7159,"name":"Ukhyun Jo","orcid":"0000-0002-2826-1355","position":5,"is_corresponding":false},{"id":1383219,"name":"Lauren Escobedo","orcid":null,"position":6,"is_corresponding":false},{"id":250445,"name":"Tapan K. Maity","orcid":"0009-0003-0184-0239","position":7,"is_corresponding":false},{"id":278617,"name":"Liton Kumar Saha","orcid":"0000-0003-3391-280X","position":8,"is_corresponding":false},{"id":491964,"name":"Isabel Uribe","orcid":"0000-0003-4092-3398","position":9,"is_corresponding":false},{"id":1077037,"name":"Sourav Saha","orcid":"0000-0002-0854-5991","position":10,"is_corresponding":false},{"id":329462,"name":"Shunichi Takeda","orcid":"0000-0002-7924-7991","position":11,"is_corresponding":false},{"id":236295,"name":"Anthony K. L. Leung","orcid":"0000-0001-5569-4036","position":12,"is_corresponding":false},{"id":1382746,"name":"Ken Chih-Chien Cheng","orcid":"0000-0001-5764-0648","position":13,"is_corresponding":false},{"id":232027,"name":"Yves Pommier","orcid":"0000-0002-3108-0758","position":14,"is_corresponding":false},{"id":261930,"name":"Yilun Sun","orcid":"0000-0002-6249-2704","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:48:54.768083Z","pmid":"39792662","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}