This renewal application is to continue work on how cyclins drive the cell cycle. The role of multi-site phosphorylation of the G1 stabilizers Sic1 and Cdh1. The G1 period of the cell cycle is refractory to B-type cyclin dependent kinase because of accumulation of the Sid stoichiometric inhibitor, and because of highly active B-type cyclin proteolysis due to Cdh1. Multi-site phosphorylation of both Sic1 and Cdh1 by G1 cyclins have been considered essential for exit from G1. We have found, though, that expression of unphosphorylatable Sic1 (all 9 Cdk sites mutated) from the endogenous locus results in a fully viable strain, though with a lengthened G1. We will similarly test the properties of unphosphorylatable Cdh1 expressed from the endogenous promoter. These experiments will address the dynamic consequences of multisite phosphorylation of G1 regulators by cyclin-Cdk complexes, at physiological levels. Interactions of B-type cyclins with cell cycle execution machinery. While a lot is known about the cell cycle oscillator controlling levels of cyclin-dependent kinase and anaphase-promoting complex, much less is known about how these activities eventually drive the actual events of the cell cycle such as DMAreplication or spindle function. Our recent results indicate that the high degree of redundancy of the six yeast B-type cyclin genes is only apparent: non-essential 'checkpoint'surveillance mechanisms and other regulatory safeguards become essential in the absence of cyclin-specific pathways. Disabling these regulatory safeguards allows focus on cell biological pathways controlled by specific cyclins. Cdc14: targets and regulators. Cdc14 is a phosphatase required for exit from mitosis;it is released from sequestration in the nucleolus just before mitotic exit. Cdc14 probably dephosphorylates Cdk targets and thus helps reverse the mitotic state, but it is unresolved if Cdc14 is specific in vivo for a few critical targets, or alternatively dephosphorylates most or all Cdk substrates. We have exploited mutants affecting Cdc14 localization to explore the spectrum of Cdc14 targets. In additional studies we will determine the consequences of blocking Pds1 degradation, at endogenous expression levels, and the functional significance of Cdk-mediated phosphorylation of the mitotic exit kinase Dbf2. These experiments will probe the dynamic consequences of Clb kinase-Cdc14 phosphatase antagonism in cell cycle regulation. Overall, we are interested in regulation of cell cycle dynamics, and in cyclin-specific pathways promoting individual cell cycle events.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear Dynamics and Transport (NDT)
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Hamlet, Michelle R
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Rockefeller University
Other Domestic Higher Education
New York
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Li, Yinyin; Cross, Frederick R; Chait, Brian T (2014) Method for identifying phosphorylated substrates of specific cyclin/cyclin-dependent kinase complexes. Proc Natl Acad Sci U S A 111:11323-8
Cross, Frederick R; Pecani, Kresti (2011) Efficient and rapid exact gene replacement without selection. Yeast 28:167-79
Rosenberg, Jessica S; Cross, Frederick R; Funabiki, Hironori (2011) KNL1/Spc105 recruits PP1 to silence the spindle assembly checkpoint. Curr Biol 21:942-7
Cross, Frederick R; Buchler, Nicolas E; Skotheim, Jan M (2011) Evolution of networks and sequences in eukaryotic cell cycle control. Philos Trans R Soc Lond B Biol Sci 366:3532-44
Oikonomou, Catherine; Cross, Frederick R (2011) Rising cyclin-CDK levels order cell cycle events. PLoS One 6:e20788
Wäsch, R; Robbins, J A; Cross, F R (2010) The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression. Oncogene 29:1-10
Oikonomou, Catherine; Cross, Frederick R (2010) Frequency control of cell cycle oscillators. Curr Opin Genet Dev 20:605-12
Robbins, Jonathan A; Cross, Frederick R (2010) Requirements and reasons for effective inhibition of the anaphase promoting complex activator CDH1. Mol Biol Cell 21:914-25
Lu, Ying; Cross, Frederick R (2010) Periodic cyclin-Cdk activity entrains an autonomous Cdc14 release oscillator. Cell 141:268-79
Ikui, Amy E; Cross, Frederick R (2009) Specific genetic interactions between spindle assembly checkpoint proteins and B-Type cyclins in Saccharomyces cerevisiae. Genetics 183:51-61

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