{"doi":"10.1093/nar/gkaf447","title":"SARS-CoV-2 point mutations are over-represented in terminal loops of RNA stem-loop structures that can be resolved by Nsp13 helicase in a unique manner with respect to nucleotide dependence","abstract":"To improve health outcomes for COVID-19 (coronavirus disease 2019) patients, the factors that influence coronavirus genome variation need to be ascertained. The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) genome is rich in predicted RNA secondary structures, particularly stem-loops (SLs) formed by intramolecular base pairing within palindromic sequences. We analyzed the NCBI Virus collection of SARS-CoV-2 genome sequences from COVID-19 individuals to map variants relative to SL structural elements. Point mutations in the SARS-CoV-2 genome, with a C-to-U transition bias, were over-represented in unpaired nucleotides and, more specifically, within the terminal loops of RNA SL structures. As the sole helicase encoded by SARS-CoV-2, Nsp13 may operate in the timely resolution of secondary RNA structures to facilitate SARS-CoV-2 RNA copying or processing. We characterized Nsp13 to resolve SARS-CoV-2 sequence-derived unimolecular RNA SL substrates and determined that it does so in a functionally cooperative manner. In addition to ATP, Nsp13 resolves the unimolecular RNA SL structure in the absence of nucleotide, in contrast to the strict ATP requirement for a bimolecular RNA forked duplex. We suggest a model in which a series of binary and ternary complex interactions of Nsp13 with nucleotide and/or RNA SL pose mechanistic implications for RNA SL resolution.","journal":"Nucleic Acids Research","year":2025,"id":521280,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9442,"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":1392116,"name":"Andrew Y Zheng","orcid":null,"position":1,"is_corresponding":false},{"id":345042,"name":"Thomas Bütler","orcid":"0000-0003-3180-9868","position":2,"is_corresponding":false},{"id":717572,"name":"Tomasz Kulikowicz","orcid":null,"position":3,"is_corresponding":false},{"id":1392117,"name":"Joe C George","orcid":null,"position":4,"is_corresponding":false},{"id":1392118,"name":"Pierce T Bombard","orcid":null,"position":5,"is_corresponding":false},{"id":246628,"name":"Joshua A. Sommers","orcid":"0000-0003-0859-6286","position":6,"is_corresponding":false},{"id":345051,"name":"Jun Ding","orcid":"0000-0002-4302-5027","position":7,"is_corresponding":false},{"id":246637,"name":"Robert M. Brosh","orcid":"0000-0003-2676-4327","position":8,"is_corresponding":false},{"id":1036786,"name":"Adaira J Dumm","orcid":"0000-0002-9495-6876","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:49:44.558743Z","pmid":"40421800","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":[]}