Commitment to cell division depends on cells growing to a certain size, called the critical size. The main objective of this proposal is to find out why critical size must be achieved, and what it is about size that allows the cell cycle to go forward. Previously, we discovered that size is linked to the steady-state levels of a critical G1 cyclin called Cln3 in yeast, whose homolog in mammalian cells is cyclin D. It appears that Cln3 is titrated against the number of DNA-bound SBF transcription factor complexes in the cell, and the number of these is simply set by genomic sequence. That is, the amount of Cln3, which grows as the cells grow, is titrated against something fixed, the number of DNA binding sites for a transcription factor complex. This allows cells to measure critical size. In the first two Aims, we will confirm, extend, and explore this titration model, in S. cerevisiae, and also in other species, to establish the generality of this mechanism. In addition, we have found that size control mechanisms remain even when the Cln3 pathway is abolished. One of these additional size control mechanisms seems to apply only in slowly growing, carbon-limited cells, and that mechanism seems to involve a cellular measurement of the storage carbohydrates glycogen and trehalose. In the third Aim, we will explore this new mechanism, with particular attention to the possibility that metabolic control pathways, and cell cycle control pathways, are more directly connected that is generally appreciated. These studies could be related to the Warburg effect in cancer cells.

Public Health Relevance

We will study the mechanism of how cells commit to a round of cell division, and in particular how and why cells must grow to a certain critical size before they can undertake division. Cancer is a disease of persistent, inappropriate cell division, and the mechanisms regulating commitment are often defective in cancer cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Hamlet, Michelle R
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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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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