The cell cycle seems to be controlled by a molecular machine that generates and regulates its own oscillations. This machine has an important point of action in G1 phase called """"""""commitment"""""""" or """"""""the restriction point"""""""" in mammalian cells, and called Start in yeast. The machine adjusts the abundance and protein kinase activity of a set of cyclin-Cdc28 complexes. The ultimate goal of this project is to find out what the molecular machine is, how it works, and what it does at Start. One specific goal is to characterize the components of the machine, such as the G1 cyclins, by a mixture of genetic and biochemical analysis. A second goal is to identify and characterize the phosphorylated substrates of the cyclin-Cdc28 complexes using a genetic screen developed by S. Fields for unknown proteins that physically interact with a known protein. A third goal is to examine the relationship between growth rate and the cyclin-Cdc28 kinase activity using immunological reagents against the Cln proteins. A fourth goal is to find out how the machine is reset after Start has occurred by seeing whether direct inhibition of the kinase activity is involved, and by looking for mutants that cannot reset. It appears that the cell cycle control mechanisms used by yeast are fundamentally similar to those used by mammalian cells. Many major medical problems such as cancer, aging, wound healing are cell cycle control problems, and may be better managed when we have a better idea of the fundamental mechanisms involved.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039978-08
Application #
2180126
Study Section
Microbial Physiology and Genetics Subcommittee 2 (MBC)
Project Start
1988-04-01
Project End
1997-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
8
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Gao, Shujuan; Honey, Sangeet; Futcher, Bruce et al. (2016) The non-homologous end-joining pathway of S. cerevisiae works effectively in G1-phase cells, and religates cognate ends correctly and non-randomly. DNA Repair (Amst) 42:1-10
Zhao, Gang; Chen, Yuping; Carey, Lucas et al. (2016) Cyclin-Dependent Kinase Co-Ordinates Carbohydrate Metabolism and Cell Cycle in S. cerevisiae. Mol Cell 62:546-57
Garg, Angad; Futcher, Bruce; Leatherwood, Janet (2015) A new transcription factor for mitosis: in Schizosaccharomyces pombe, the RFX transcription factor Sak1 works with forkhead factors to regulate mitotic expression. Nucleic Acids Res 43:6874-88
Cai, Ying; Futcher, Bruce (2013) Effects of the yeast RNA-binding protein Whi3 on the half-life and abundance of CLN3 mRNA and other targets. PLoS One 8:e84630
Ferrezuelo, Francisco; Colomina, Neus; Futcher, Bruce et al. (2010) The transcriptional network activated by Cln3 cyclin at the G1-to-S transition of the yeast cell cycle. Genome Biol 11:R67
Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M et al. (2009) Daughter-specific transcription factors regulate cell size control in budding yeast. PLoS Biol 7:e1000221
Wang, Hongyin; Carey, Lucas B; Cai, Ying et al. (2009) Recruitment of Cln3 cyclin to promoters controls cell cycle entry via histone deacetylase and other targets. PLoS Biol 7:e1000189
Honey, Sangeet; Futcher, Bruce (2007) Roles of the CDK phosphorylation sites of yeast Cdc6 in chromatin binding and rereplication. Mol Biol Cell 18:1324-36
Jorgensen, Paul; Edgington, Nicholas P; Schneider, Brandt L et al. (2007) The size of the nucleus increases as yeast cells grow. Mol Biol Cell 18:3523-32
Futcher, Bruce (2006) Metabolic cycle, cell cycle, and the finishing kick to Start. Genome Biol 7:107

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