{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:32:22Z","timestamp":1791588742840,"version":"4.3.4"},"posted":{"date-parts":[[2023,12,13]]},"group-title":"Biochemistry","reference-count":55,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,12,13]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Expansion of trinucleotide repeats causes Huntington\u2019s disease, Fragile X syndrome and over twenty other monogenic disorders\n                  <jats:sup>1<\/jats:sup>\n                  . How mismatch repair protein MutS\u03b2 and large repeats of CNG (N=A, T, C or G) cooperate to drive the expansion is poorly understood. Contrary to expectations, we find that MutS\u03b2 prefers to bind the stem of an extruded (CNG) hairpin rather than the hairpin end or hairpin-duplex junction. Structural analyses reveal that in the presence of MutS\u03b2, CNG repeats with N:N mismatches adopt a B form-like pseudo-duplex, with one or two CNG repeats slipped out forming uneven bubbles that partly mimic insertion-deletion loops of mismatched DNA\n                  <jats:sup>2<\/jats:sup>\n                  . When the extruded hairpin exceeds 40-45 repeats, it can be bound by three or more MutS\u03b2 molecules, which are resistant to ATP-dependent dissociation. We envision that such MutS\u03b2-CNG complexes recruit MutL\u03b3 endonuclease to nick DNA and initiate the repeat expansion process\n                  <jats:sup>3,4<\/jats:sup>\n                  . To develop drugs against the expansion diseases, we have identified lead compounds that prevent MutS\u03b2 binding to CNG repeats but not to mismatched DNA.\n                <\/jats:p>","DOI":"10.1101\/2023.12.12.571350","type":"posted-content","created":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T20:40:17Z","timestamp":1702500017000},"source":"Crossref","is-referenced-by-count":4,"title":["Tandem MutS\u03b2 binding to long extruded DNA trinucleotide repeats underpins pathogenic expansions"],"prefix":"10.64898","author":[{"given":"Jun","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaibin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023121803162430000_2023.12.12.571350v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2015.11.008"},{"key":"2023121803162430000_2023.12.12.571350v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2175"},{"key":"2023121803162430000_2023.12.12.571350v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature05778"},{"key":"2023121803162430000_2023.12.12.571350v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1914718117"},{"key":"2023121803162430000_2023.12.12.571350v1.5","doi-asserted-by":"publisher","DOI":"10.1042\/BST20200143"},{"key":"2023121803162430000_2023.12.12.571350v1.6","doi-asserted-by":"publisher","DOI":"10.1017\/erm.2022.16"},{"key":"2023121803162430000_2023.12.12.571350v1.7","first-page":"5853","article-title":"Microsatellite 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