Harris, MR; (2014) G1/S transcriptional regulation in Saccharomyces cerevisiae integrates cell cycle progression and genome stability. Doctoral thesis , UCL (University College London).

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Abstract

Saccharomyces cerevisiae provides an ideal model to study the regulation of cell cycle commitment due to the high conservation of signalling pathways and regulatory modules through to higher eukaryotes. My work investigates the interplay of cell cycle progression and arrest via the action of transcription factor regulation. Cell cycle commitment is controlled by the cyclin-dependent activation of transcription factor complexes, MBF and SBF. Here I describe the dynamics of SBF and MBF using new polyclonal anti-sera against the three key components Mbp1, Swi4 and Swi6, and their interaction with the inhibitor of SBF, Whi5, and the MBF co-repressor Nrm1. I identify epigenetic modifications that occur on histone proteins at promoters of SBF and MBF genes during the cell cycle. The histone deacetylase Rpd3 has also been investigated as to the role it plays in regulating G1/S transcription. Finally, I have identified a new class of G1/S genes, named switch genes, which are regulated independently by G1/S transcription factors during different phases of the cell cycle. Switch genes are regulated by SBF during G1 and MBF upon entry into S phase, and are enriched for dosage sensitive and replication induced G1/S genes. Switching from SBF-to-MBF allows genes to be activated in response to replication stress, via inactivation of Nrm1. In addition, through switching a potential defect in one of the transcriptional factor complexes will not result in overexpression of these genes. Detailed analysis of the prototypical switch gene TOS4 shows that it is regulated by SBF and MBF, accumulates in response to hydroxyurea, and delays cell cycle progression when over-expressed. The role Tos4 plays in the cell cycle and in response to checkpoint activation remains unclear, however, data suggests a role in modulating HDAC activity. The roles other switch genes play in response to checkpoint activation are yet to be investigated.

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