{"doi":"10.1093/nar/gkaf646","title":"A human high-fidelity DNA polymerase holoenzyme has a wide range of lesion bypass activities","abstract":"During replication, lagging strand lesions are initially encountered by high-fidelity DNA polymerase (pol) holoenzymes comprised of pol δ and the PCNA sliding clamp. To proceed unhindered, pol δ holoenzymes must bypass lesions without stalling. This entails dNMP incorporation opposite the lesion (insertion) and the 5' template deoxynucleotide (extension). Historically, it was viewed that high-fidelity pol holoenzymes stall upon encountering lesions, activating DNA damage tolerance pathways that are ultimately responsible for lesion bypass. Our recent study of four prominent lesions revealed that human pol δ holoenzymes support insertion and/or bypass for multiple lesions and the extent of these activities depends on the lesion and pol δ proofreading. In the present study, we expand these analyses to other prominent lesions. Collectively, analyses of 10 lesions from both studies reveal that the insertion and bypass efficiencies of pol δ holoenzymes each span a complete range (0%-100%). Consequently, the fates of pol δ holoenzymes upon encountering lesions are quite diverse. Furthermore, pol δ proofreading promoted holoenzyme progression at 7 of the 10 lesions and did not deter progression at any. Altogether, the results significantly alter our understanding of the replicative capacity of high-fidelity pol holoenzymes and their functional role(s) in lesion bypass.","journal":"Nucleic Acids Research","year":2025,"id":553567,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"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":956252,"name":"Joseph A. Cardina","orcid":null,"position":1,"is_corresponding":false},{"id":1450542,"name":"Helen Washington","orcid":null,"position":2,"is_corresponding":false},{"id":1121992,"name":"Shijun Gao","orcid":null,"position":3,"is_corresponding":false},{"id":387543,"name":"Marc M. Greenberg","orcid":"0000-0002-5786-6118","position":4,"is_corresponding":false},{"id":415429,"name":"Mark Hedglin","orcid":"0000-0003-2599-1691","position":5,"is_corresponding":false},{"id":956251,"name":"Rachel L. Dannenberg","orcid":null,"position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T02:54:41.819682Z","pmid":"40671520","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":[]}