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Role of a metabolic burst and titration of an unstable activator in the entrainment of division to growth

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dc.contributor.advisor Futcher, Bruce en_US
dc.contributor.author Carey, Lucas Buckler en_US
dc.contributor.other Department of Genetics en_US
dc.date.accessioned 2012-05-15T18:02:25Z
dc.date.accessioned 2015-04-24T14:45:17Z
dc.date.available 2012-05-15T18:02:25Z
dc.date.available 2015-04-24T14:45:17Z
dc.date.issued 2010-05-01
dc.identifier Carey_grad.sunysb_0771E_10015.pdf en_US
dc.identifier.uri http://hdl.handle.net/1951/55381 en_US
dc.identifier.uri http://hdl.handle.net/11401/70956 en_US
dc.description.abstract Most cells coordinate increase in mass with an increase in cell number. Using simu- lations I show that exponentially growing cells require size control (a molecular link between growth and division) to maintain a population with a biologically reasonable cell size distribution, though linearly growing cells do not. The main regulator of cell-cycle commitment in budding yeast is the G1 cyclin Cln3, which partners with the Cyclin Dependent Kinase (CDK) Cdc28 to activate the transcription factor SBF and promote transcription of over 150 genes involved in cell-cycle progression. Commitment to Start (passage from G1 into S) involves transition from a low Cyclin/CDK state to a high Cyclin/CDK state, and this transition is driven largely by Cln3/CDK activity. Cln3 is recruited indirectly to DNA by SBF where it both activates transcriptional activators and inhibits transcriptional repressors. Cln3 is unstable, so the amount of Cln3 in cells is proportional to their size (biosynthetic capacity). By measuring cell volume throughout the cell-cycle we show that addition of more SBF binding sites increases cell size, and that this increase varies depending on the genetic dose of CLN3. This suggests that cells may measure size by titrating an unknown and noisy amount of Cln3 protein to a known and constant number of SBF binding sites. Slowly growing cells produce less cyclinprotein per unit mRNA than do rapidly growing cells. Using a genetic system in which I can tightly control the level of cyclin expression I show that slowly growing cells require less cyclin expression to pass through Start; this growth dependent threshold requirement may be a result of the instability of Cln3. Finally, I show that in addition to the transcrip- tional positive feedback loop that switches cells from low Cln/CDK to high Cln/CDK, there may be contribution from a metabolic feedback loop in which Cyclin/CDK activity may drive, and be driven by, metabolic changes during Start. These metabolic changes involve the sudden conversion of stored carbohydrate (glycogen and trehalose) to glucose in late G1 phase. I show that carbohydrate mutants have cell-size phenotypes, that genes involved in carbohydrate metabolism are CDK targets and that genes involved in cell- cycle control are Protein Kinase A (PKA) targets. I show that there is a spike in PKA activity around Start, and that the transcriptional profile around Start in ethanol grown cells is similar to that of ethanol grown cells spiked with glucose. These results suggest that slowly growing carbon-deprived cells briefly become rapidly growing carbon-rich cells around Start, and this increase in biosynthetic capacity may drive cells through Start. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Biology, Genetics en_US
dc.subject.other cell cycle, genetics, metabolism, yeast en_US
dc.title Role of a metabolic burst and titration of an unstable activator in the entrainment of division to growth en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Rolf Sternglanz en_US
dc.contributor.committeemember Aaron Neimann en_US
dc.contributor.committeemember John Reinitz en_US
dc.contributor.committeemember Robert Haltiwanger. en_US

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