{"doi":"10.1093/nar/gkaf299","title":"Molecular basis for RNA discrimination by human DNA ligase 1","abstract":"DNA ligase 1 (LIG1) finalizes DNA replication and repair by catalyzing the joining of DNA nicks. LIG1 is highly specific for DNA-DNA junctions over DNA-RNA junctions, discriminating strongly against a single ribonucleotide at the 5' side of the nick. This selectivity of LIG1 prevents futile and potentially mutagenic DNA-RNA cleavage and re-ligation cycles during Okazaki fragment maturation or ribonucleotide excision repair of genome-embedded ribonucleotide monophosphates (rNMPs), but the determinants of LIG1 rNMP discrimination are ill-defined. We report structural and kinetic analysis of LIG1 DNA-RNA complexes showing that LIG1 employs an aromatic steric gate to stabilize the enzyme-substrate complex and directly exclude rNMP-containing polynucleotides. Mutation of this RNA gate compromises the adenylyl-transfer and nick-sealing reactions but decreases the discrimination against an rNMP-containing substrate by ∼3600-fold. Our results establish the role of the conserved steric gate in ribonucleotide discrimination by high-fidelity (HiFi) DNA ligases at each step of the ligation reaction, which has parallels to the ribonucleotide discrimination by HiFi DNA polymerases.","journal":"Nucleic Acids Research","year":2025,"id":543782,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"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":0.9592,"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":705472,"name":"Thomas J. Jurkiw","orcid":"0000-0001-9624-4568","position":1,"is_corresponding":false},{"id":398021,"name":"J.M. Krahn","orcid":"0000-0002-4640-0267","position":2,"is_corresponding":false},{"id":1434105,"name":"Neha V Bokil","orcid":null,"position":3,"is_corresponding":false},{"id":449951,"name":"Suzanne J. Admiraal","orcid":"0000-0003-3334-2499","position":4,"is_corresponding":false},{"id":342596,"name":"Lars C. Pedersen","orcid":"0000-0002-4488-4077","position":5,"is_corresponding":false},{"id":598764,"name":"Jessica S. Williams","orcid":"0000-0002-9758-5812","position":6,"is_corresponding":false},{"id":73052,"name":"Thomas A. Kunkel","orcid":"0000-0002-9900-1788","position":7,"is_corresponding":false},{"id":449952,"name":"Patrick O’Brien","orcid":"0000-0001-7853-8626","position":8,"is_corresponding":false},{"id":225589,"name":"R. Scott Williams","orcid":"0000-0002-4610-8397","position":9,"is_corresponding":false},{"id":662643,"name":"Percy Tumbale","orcid":null,"position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:53:08.338070Z","pmid":"40239996","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":[]}