Dividing cells must co-ordinate their rate of division with their rate of cell growth and protein synthesis. In many microbes, and in yeast in particular, this co-ordination is achieved by a size control mechanism: when the cell grows to a certain """"""""critical size"""""""", it triggers commitment to the cell cycle. Thus division depends on growth. Our central interest is in understanding how """"""""critical size"""""""" is measured or determined by the cell;in other words, mechanistically, what is it about growth to a certain size that allows cells to commit to the cell cycle? In S. cerevisiae, it has long been recognized that the G1 cyclin Cln3 plays a role in this co-ordination. At critical cell size, a Cln3-Cdc28 kinase activates the transcription factors SBF and MBF, which in turn induce the transcription of over 200 genes important for cell cycle progress into S-phase. More recently, we have found preliminary evidence for two additional mechanisms of size control, one involving translation, and one involving accumulation of storage carbohydrates. Here, we will study these three mechanisms of size control. First, we will study the mechanism by which Cln3 activates the SBF transcription factor, and why this activation is size-dependent. An exciting recent result suggests that the amount of Cln3 is being titrated against the number of SBF binding sites in the genome, and this constitutes the size measurement device. Second, we will study size-dependent changes in the quality and quantity of translation. These changes may be influenced by the size control genes WHI3 and WHI4, and by the mysterious """"""""translation factor"""""""" Tif51. Third, for cells growing under poor nutrient conditions, another kind of size control appears, and this size control measures the levels of internal storage carbohydrates (glycogen and trehalose). We will characterize and explore this mechanism. These three pathways have interconnections and crosstalk. All three of these pathways may have analogous if not homologous pathways in mammalian cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039978-20
Application #
7661537
Study Section
Cellular Signaling and Dynamics Study Section (CSD)
Program Officer
Zatz, Marion M
Project Start
1988-04-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
20
Fiscal Year
2009
Total Cost
$322,312
Indirect Cost
Name
State University New York Stony Brook
Department
Genetics
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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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