{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T12:48:32Z","timestamp":1782046112971,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,18]]},"group-title":"Genetics","reference-count":95,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01HD041012"],"award-info":[{"award-number":["R01HD041012"]}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01HD097987"],"award-info":[{"award-number":["R01HD097987"]}]},{"name":"National Cancer Institute","award":["R01CA248536"],"award-info":[{"award-number":["R01CA248536"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,18]]},"abstract":"<jats:title>\n                  <jats:bold>SUMMARY<\/jats:bold>\n                <\/jats:title>\n                <jats:p>\n                  Meiotic recombination initiates with DNA double-strand breaks (DSBs) repaired as either crossovers (COs) or non-crossovers. Across eukaryotes, MSH4\/MSH5 (MutS\u03b3) licenses DSB repair intermediates, directing repair into the class I CO pathway via recruitment of MLH1\/MLH3 (MutL\u03b3). In mammals, excess MutS\u03b3 sites relative to final MutL\u03b3 foci suggest additional MutS\u03b3 functions, including directing repair through the minor class II CO pathway. We investigated the role of a mammalian-specific 38-amino acid C-terminal domain of MSH5 using mice lacking this domain (\n                  <jats:italic>\n                    Msh5\n                    <jats:sup>\u0394C\/\u0394C<\/jats:sup>\n                  <\/jats:italic>\n                  ). Spermatocytes and oocytes load MSH4 normally to achieve CO licensing in zygonema, but these numbers decline precipitously in pachynema, leading to dramatically reduced MutL\u03b3 foci and associated pro-CO factors HEI10 and CNTD1. Despite this, licensing factors RNF212B and MutS\u03b3-associated kinase CDK4 remain persistently upregulated in pachynema. Strikingly, the switch from licensing-associated CDK4 to CO-site-associated CDK2 fails to occur in\n                  <jats:italic>\n                    Msh5\n                    <jats:sup>\u0394C\/\u0394C<\/jats:sup>\n                  <\/jats:italic>\n                  mice, even at residual class I CO events. The result is rapid germ cell death prior to prophase I completion in both sexes. Thus, the loss of the MSH5 C-terminus functionally uncouples the regulatory proteins that define the stepwise patterning of class I COs. Our findings reveal novel early roles for the C-terminus of mammalian MSH5 in converting licensed DSB repair intermediates to designated class I COs.\n                <\/jats:p>","DOI":"10.64898\/2026.06.16.731784","type":"posted-content","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T18:00:22Z","timestamp":1781805622000},"source":"Crossref","is-referenced-by-count":0,"title":["A mammalian-specific domain of MSH5 drives the transition from crossover licensing to designation during meiotic prophase I"],"prefix":"10.64898","author":[{"given":"Ky\u2019ara D.","family":"Carr","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Cornell Reproductive Sciences Center (CoRe), Cornell University, Ithaca, NY 14853"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliza","family":"O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Cornell Reproductive Sciences Center (CoRe), Cornell 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