{"doi":"10.1093/nar/gkad934","title":"Elevated MSH2 MSH3 expression interferes with DNA metabolism <i>in vivo</i>","abstract":"The Msh2-Msh3 mismatch repair (MMR) complex in Saccharomyces cerevisiae recognizes and directs repair of insertion/deletion loops (IDLs) up to ∼17 nucleotides. Msh2-Msh3 also recognizes and binds distinct looped and branched DNA structures with varying affinities, thereby contributing to genome stability outside post-replicative MMR through homologous recombination, double-strand break repair (DSBR) and the DNA damage response. In contrast, Msh2-Msh3 promotes genome instability through trinucleotide repeat (TNR) expansions, presumably by binding structures that form from single-stranded (ss) TNR sequences. We previously demonstrated that Msh2-Msh3 binding to 5' ssDNA flap structures interfered with Rad27 (Fen1 in humans)-mediated Okazaki fragment maturation (OFM) in vitro. Here we demonstrate that elevated Msh2-Msh3 levels interfere with DNA replication and base excision repair in vivo. Elevated Msh2-Msh3 also induced a cell cycle arrest that was dependent on RAD9 and ELG1 and led to PCNA modification. These phenotypes also required Msh2-Msh3 ATPase activity and downstream MMR proteins, indicating an active mechanism that is not simply a result of Msh2-Msh3 DNA-binding activity. This study provides new mechanistic details regarding how excess Msh2-Msh3 can disrupt DNA replication and repair and highlights the role of Msh2-Msh3 protein abundance in Msh2-Msh3-mediated genomic instability.","journal":"Nucleic Acids Research","year":2023,"id":351930,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1008471,"name":"Samantha Phelps","orcid":null,"position":1,"is_corresponding":false},{"id":1008244,"name":"Madhumita Sridharan","orcid":"0000-0002-2626-7809","position":2,"is_corresponding":false},{"id":690780,"name":"Jordan T. Becker","orcid":"0000-0002-0239-5443","position":3,"is_corresponding":false},{"id":724828,"name":"Natalie A. Lamb","orcid":"0000-0002-2774-9586","position":4,"is_corresponding":false},{"id":644679,"name":"Charanya Kumar","orcid":"0000-0001-7678-9288","position":5,"is_corresponding":false},{"id":648680,"name":"Mark D. Sutton","orcid":"0000-0002-8221-9297","position":6,"is_corresponding":false},{"id":263507,"name":"Anja‐Katrin Bielinsky","orcid":"0000-0003-1783-619X","position":7,"is_corresponding":false},{"id":452475,"name":"Lata Balakrishnan","orcid":"0000-0003-0285-9559","position":8,"is_corresponding":false},{"id":1008245,"name":"Jennifer A. Surtees","orcid":"0000-0003-4243-0933","position":9,"is_corresponding":false},{"id":1008243,"name":"Melisa Medina‐Rivera","orcid":"0000-0001-7074-5663","position":0,"is_corresponding":true}],"reference_count":156,"raw_metadata":null,"created_at":"2026-07-19T01:12:45.897709Z","pmid":"37930834","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":[]}