title: Quantitative proteomics reveals the basis for the biochemical specificity of the cell-cycle machinery.
abstract: Cyclin-dependent kinases comprise the conserved machinery that drives progress through the cell cycle, but how they do this in mammalian cells is still unclear. To identify the mechanisms by which cyclin-cdks control the cell cycle, we performed a time-resolved analysis of the in vivo interactors of cyclins E1, A2, and B1 by quantitative mass spectrometry. This global analysis of context-dependent protein interactions reveals the temporal dynamics of cyclin function in which networks of cyclin-cdk interactions vary according to the type of cyclin and cell-cycle stage. Our results explain the temporal specificity of the cell-cycle machinery, thereby providing a biochemical mechanism for the genetic requirement for multiple cyclins in vivo and reveal how the actions of specific cyclins are coordinated to control the cell cycle. Furthermore, we identify key substrates (Wee1 and c15orf42/Sld3) that reveal how cyclin A is able to promote both DNA replication and mitosis.
authors.affiliation: The Gurdon Institute, University of Cambridge, Cambridge, UK.
authors.forename: Felicia Walton
authors.initials: FW
authors.lastname: Pagliuca
authors.forename: Mark O
authors.initials: MO
authors.lastname: Collins
authors.forename: Agata
authors.initials: A
authors.lastname: Lichawska
authors.forename: Philip
authors.initials: P
authors.lastname: Zegerman
authors.forename: Jyoti S
authors.initials: JS
authors.lastname: Choudhary
authors.forename: Jonathon
authors.initials: J
authors.lastname: Pines
mesh_terms: D000595:Amino Acid Sequence; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D056751:Cyclin A2 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D056744:Cyclin B1 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D019927:Cyclin E / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D004261:DNA Replication; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D016415:Sequence Alignment; D013379:Substrate Specificity
chemical_list: C503721:CCNA2 protein, human; C534699:CCNB1 protein, human; C475820:CCNE1 protein, human; D018797:Cell Cycle Proteins; D056751:Cyclin A2; D056744:Cyclin B1; D019927:Cyclin E; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C547406:TICRR protein, human; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D018844:Cyclin-Dependent Kinases