{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:11:23Z","timestamp":1787008283113,"version":"build-2736575974"},"reference-count":59,"publisher":"American Society for Cell Biology (ASCB)","issue":"25","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:p>\n                    The earliest step in DNA replication is origin licensing, which is the DNA loading of minichromosome maintenance (MCM) helicase complexes. The Cdc10-dependent transcript 1 (Cdt1) protein is essential for MCM loading during the G1 phase of the cell cycle, but the mechanism of Cdt1 function is still incompletely understood. We examined a collection of rare Cdt1 variants that cause a form of primordial dwarfism (the Meier\u2013Gorlin syndrome) plus one hypomorphic Drosophila allele to shed light on Cdt1 function. Three hypomorphic variants load MCM less efficiently than wild-type (WT) Cdt1, and their lower activity correlates with impaired MCM binding. A structural homology model of the human Cdt1\u2013MCM complex positions the altered Cdt1 residues at two distinct interfaces rather than the previously described single MCM interaction domain. Surprisingly, one dwarfism allele ( Cdt1-A66T) is more active than WT Cdt1. This hypermorphic variant binds both cyclin A and SCF\n                    <jats:sup>Skp2<\/jats:sup>\n                    poorly relative to WT Cdt1. Detailed quantitative live-cell imaging analysis demonstrated no change in the stability of this variant, however. Instead, we propose that cyclin A\/CDK inhibits the Cdt1 licensing function independent of the creation of the SCF\n                    <jats:sup>Skp2<\/jats:sup>\n                    phosphodegron. Together, these findings identify key Cdt1 interactions required for both efficient origin licensing and tight Cdt1 regulation to ensure normal cell proliferation and genome stability.\n                  <\/jats:p>","DOI":"10.1091\/mbc.e18-04-0242","type":"journal-article","created":{"date-parts":[[2018,10,3]],"date-time":"2018-10-03T13:52:20Z","timestamp":1538574740000},"page":"2989-3002","source":"Crossref","is-referenced-by-count":15,"title":["Cdt1 variants reveal unanticipated aspects of interactions with cyclin\/CDK and MCM important for normal genome replication"],"prefix":"10.1091","volume":"29","author":[{"given":"Pedro N.","family":"Pozo","sequence":"first","affiliation":[{"name":"Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob P.","family":"Matson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasemin","family":"Cole","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna M.","family":"Kedziora","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin D.","family":"Grant","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Temple","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"},{"name":"R. 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