{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:35:01Z","timestamp":1791272101875,"version":"4.1.0"},"reference-count":39,"publisher":"American Society for Cell Biology (ASCB)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2014,2,15]]},"abstract":"<jats:p>Cdh1, a coactivator of the anaphase-promoting complex (APC), is a potential tumor suppressor. Cdh1 ablation promotes precocious S-phase entry, but it was unclear how this affects DNA replication dynamics while contributing to genomic instability and tumorigenesis. We find that Cdh1 depletion causes early S-phase onset in conjunction with increase in Rb\/E2F1-mediated cyclin E1 expression, but reduced levels of cyclin E1 protein promote this transition. We hypothesize that this is due to a weakened cyclin-dependent kinase inhibitor (CKI)\u2013cyclin-dependent kinase 2 positive-feedback loop, normally generated by APC-Cdh1\u2013mediated proteolysis of Skp2. Indeed, Cdh1 depletion increases Skp2 abundance while diminishing levels of the CKI p27. This lowers the level of cyclin E1 needed for S-phase entry and delays cyclin E1 proteolysis during S-phase progression while corresponding to slowed replication fork movement and reduced frequency of termination events. In summary, using both experimental and computational approaches, we show that APC-Cdh1 establishes a stimulus\u2013response relationship that promotes S phase by ensuring that proper levels of p27 accumulate during G1 phase, and defects in its activation accelerate the timing of S-phase onset while prolonging its progression.<\/jats:p>","DOI":"10.1091\/mbc.e13-08-0480","type":"journal-article","created":{"date-parts":[[2013,12,20]],"date-time":"2013-12-20T00:52:12Z","timestamp":1387500732000},"page":"441-456","source":"Crossref","is-referenced-by-count":38,"title":["Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset"],"prefix":"10.1091","volume":"25","author":[{"given":"Xi","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of Biology, Indiana University, Bloomington, IN 47405-7003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeyaraman","family":"Srividhya","sequence":"additional","affiliation":[{"name":"Department of 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