Kinase-independent function of cyclin E.
E-type cyclins are thought to drive cell-cycle progression by activating cyclin-dependent kinases, primarily CDK2. We previously found that cyclin E-null cells failed to incorporate MCM helicase into DNA prereplication complex during G(0) --> S phase progression. We now report that a kinase-deficient cyclin E mutant can partially restore MCM loading and S phase entry in cyclin E-null cells. We found that cyclin E is loaded onto chromatin during G(0) --> S progression. In the absence of cyclin E, CDT1 is normally loaded onto chromatin, whereas MCM is not, indicating that cyclin E acts between CDT1 and MCM loading. We observed a physical association of cyclin E with CDT1 and with MCMs. We propose that cyclin E facilitates MCM loading in a kinase-independent fashion, through physical interaction with CDT1 and MCM. Our work indicates that-in addition to their function as CDK activators-E cyclins play kinase-independent functions in cell-cycle progression.
Geng
Yan
Y
Department of Cancer Biology, Dana-Farber Cancer Institute, USA.
Lee
Young-Mi
YM
Welcker
Markus
M
Swanger
Jherek
J
Zagozdzon
Agnieszka
A
Winer
Joel D
JD
Roberts
James M
JM
Kaldis
Philipp
P
Clurman
Bruce E
BE
Sicinski
Piotr
P
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D019927:Cyclin E / Q000172:deficiency / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009857:Oncogenes; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D016192:Resting Phase, Cell Cycle; D016196:S Phase
D018797:Cell Cycle Proteins; D002843:Chromatin; D019927:Cyclin E; D004268:DNA-Binding Proteins; D050505:Mutant Proteins; C498645:Ris2 protein, mouse; D018844:Cyclin-Dependent Kinases; D004265:DNA Helicases