{"doi":"10.1093/narcan/zcaa013","title":"XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells","abstract":"Abstract Homologous recombination/end joining (HR/HEJ)-deficient cancers with BRCA mutations utilize alternative DNA double-strand break repair pathways, particularly alternative non-homologous end joining or microhomology-mediated end joining (alt-EJ/MMEJ) during S and G2 cell cycle phases. Depletion of alt-EJ factors, including XRCC1, PARP1 and POLQ, is synthetically lethal with BRCA2 deficiency; yet, XRCC1 roles in HR-deficient cancers and replication stress are enigmatic. Here, we show that after replication stress, XRCC1 forms an active repair complex with POLQ and MRE11 that supports alt-EJ activity in vitro. BRCA2 limits XRCC1 recruitment and repair complex formation to suppress alt-EJ at stalled forks. Without BRCA2 fork protection, XRCC1 enables cells to complete DNA replication at the expense of increased genome instability by promoting MRE11-dependent fork resection and restart. High XRCC1 and MRE11 gene expression negatively impacts Kaplan–Meier survival curves and hazard ratios for HR-deficient breast cancer patients in The Cancer Genome Atlas. The additive effects of depleting both BRCA2 and XRCC1 indicate distinct pathways for replication restart. Our collective data show that XRCC1-mediated processing contributes to replication fork degradation, replication restart and chromosome aberrations in BRCA2-deficient cells, uncovering new roles of XRCC1 and microhomology-mediated repair mechanisms in HR-deficient cancers, with implications for chemotherapeutic strategies targeting POLQ and PARP activities.","journal":"NAR Cancer","year":2020,"id":62608,"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":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":307696,"name":"Albino Bacolla","orcid":"0000-0003-0206-8423","position":1,"is_corresponding":false},{"id":331241,"name":"Haibo Wang","orcid":"0000-0002-7549-5613","position":2,"is_corresponding":false},{"id":107256,"name":"Zu Ye","orcid":"0000-0003-0846-7548","position":3,"is_corresponding":false},{"id":331242,"name":"Erika N. Guerrero","orcid":"0000-0002-9838-3577","position":4,"is_corresponding":false},{"id":331243,"name":"Wei Jiang","orcid":"0000-0002-9079-0792","position":5,"is_corresponding":false},{"id":331244,"name":"Randa El‐Zein","orcid":"0000-0002-0750-4143","position":6,"is_corresponding":false},{"id":294863,"name":"Muralidhar L. Hegde","orcid":"0000-0001-7333-8123","position":7,"is_corresponding":false},{"id":309166,"name":"Alan E. Tomkinson","orcid":"0000-0002-2671-1711","position":8,"is_corresponding":false},{"id":107262,"name":"John A. Tainer","orcid":"0000-0003-1659-2429","position":9,"is_corresponding":false},{"id":331245,"name":"Sankar Mitra","orcid":"0000-0002-9053-8589","position":10,"is_corresponding":false},{"id":331240,"name":"Bradley Eckelmann","orcid":"0009-0000-2429-1066","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-18T21:10:35.996198Z","pmid":"32776008","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":[]}