title: Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset.
abstract: 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)-cyclin-dependent kinase 2 positive-feedback loop, normally generated by APC-Cdh1-mediated 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-response 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.
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405-7003 Biocomplexity Institute, Department of Physics, Indiana University, Bloomington, IN 47405-7003 Department of Environmental Health, School of Public Health, Indiana University, Bloomington, IN 47408-2671 Department of Statistics, Indiana University, Bloomington, IN 47408-3825.
authors.forename: Xi
authors.initials: X
authors.lastname: Yuan
authors.forename: Jeyaraman
authors.initials: J
authors.lastname: Srividhya
authors.forename: Thomas
authors.initials: T
authors.lastname: De Luca
authors.forename: Ju-Hyong E
authors.initials: JH
authors.lastname: Lee
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Pomerening
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000235:genetics* / Q000378:metabolism; D015703:Antigens, CD; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D016193:G1 Phase; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D016196:S Phase; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D015703:Antigens, CD; C475820:CCNE1 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D019927:Cyclin E; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D064173:Anaphase-Promoting Complex-Cyclosome; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2