Cooke, Sophie Louise; (2020) Transcriptional control during the G1 and S phases of the cell cycle in yeast. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cell division is a tightly coordinated process that involves doubling of the cellular content and its separation into two genetically identical daughter cells. In G1 phase of the cell cycle activation of the G1/S transcriptional wave initiates entry into S phase, during which the genomic DNA is replicated, and thereby activation of G1/S transcription commits cells to a new round of division. In the budding yeast, Saccharomyces cerevisiae, this transcriptional wave is controlled by two transcription factors, MBF and SBF. Previous work suggested that changes to the chromatin state through histone acetylation has an important role in regulating G1/S transcription. In this thesis I show that the HAT Gcn5 and HDAC Rpd3, which control histone acetylation, have a limited contribution to G1/S transcriptional regulation. The G1/S transcription factors MBF and SBF are highly similar, yet MBF regulates G1/S transcription through repression of its targets, and SBF through activation. My findings suggest that the local chromatin environment is unlikely to explain their opposing mechanisms. During S phase the process of DNA replication causes an imbalance in gene copy number between early- and late-replicating genes, which could alter their transcription levels. It was previously reported that S. cerevisiae exhibits gene expression homeostasis, defined as the buffering of transcription levels against DNA copy number changes during S phase. My work confirms a previously indicated requirement of the protein Tos4 in this process, and suggests this is dependent upon its binding to HDACs. I also demonstrate that Tos4, and therefore gene expression homeostasis, confers a fitness advantage. Loss of Tos4-dependent gene expression homeostasis may increase dependence upon components of the gene expression and protein production pathways. Overall this work provides new insights into transcriptional regulation at distinct cell cycle stages: in the contribution of the chromatin state to G1/S transcriptional regulation, and the control of transcription during DNA replication.

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