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In Saccharomyces cerevisiae, Msh2-Msh3 and Msh2-Msh6 initiate MMR by recognizing and binding insertion or deletion (in\/del) loops up to \u223c17 nucleotides (nt.) and base\u2013base mispairs, respectively; the 2 complexes have overlapping specificity for small (1\u20132 nt.) in\/dels. The DNA-binding specificity for the 2 complexes resides in their respective mispair binding domains (MBDs) and has distinct DNA-binding modes. Msh2-Msh3 also plays a role in promoting CAG\/CTG trinucleotide repeat (TNR) expansions, which underlie many neurodegenerative diseases such as Huntington's disease and myotonic dystrophy type 1. Models for Msh2-Msh3's role in promoting TNR tract expansion have invoked its specific DNA-binding activity and predict that the TNR structure alters its DNA binding and downstream activities to block repair. Using a chimeric Msh complex that replaces the MBD of Msh6 with the Msh3 MBD, we demonstrate that Msh2-Msh3 DNA-binding activity is not sufficient to promote TNR expansions. We propose a model for Msh2-Msh3-mediated TNR expansions that requires a fully functional Msh2-Msh3 including DNA binding, coordinated ATP binding, and hydrolysis activities and interactions with Mlh complexes that are analogous to those required for MMR.<\/jats:p>","DOI":"10.1093\/genetics\/iyae222","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T08:45:38Z","timestamp":1736498738000},"source":"Crossref","is-referenced-by-count":2,"title":["Msh2-Msh3 DNA-binding is not sufficient to promote trinucleotide repeat expansions in <i>Saccharomyces cerevisiae<\/i>"],"prefix":"10.1093","volume":"229","author":[{"given":"Katherine M","family":"Casazza","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo , Buffalo, NY 14203 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory M","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo , Buffalo, NY 14203 ,","place":["USA"]},{"name":"Curia Global, Inc. , Buffalo, NY 14203 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Johengen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo , Buffalo, NY 14203 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gavin","family":"Twoey","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo , Buffalo, NY 14203 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