Kishkevich, Anastasiya; (2017) Cell cycle regulated transcription and genome integrity in yeast. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cell cycle is composed of G1, S and G2 phases and Mitosis and is governed by waves of transcription. G1/S transcriptional wave is involved in cell cycle commitment. In my thesis, I investigate the role of histone acetylation in G1/S transcriptional regulation. In S. cerevisiae histone deacetylase Rpd3 and histone acetyltransferase Gcn5 are recruited to G1/S target gene promoters and are implicated in regulation of G1/S transcription. Here I show that acetylation of histones at G1/S promoters is cell cycle regulated. However, deletion of RPD3 or GCN5 does not lead to loss of transcriptional regulation, but only results in mild de-repression of transcription in G1 and S phase in rpd3∆ cells and not full activation at G1/S transition in gcn5∆ cells. In the thesis, I present my work and that of our collaborators from Oxford, where established that histone methyltransferase Set2-dependent H3K36me2 and H3K36me3 are necessary for activation and maintenance of G1/S transcription in response to replication stress caused by hydroxyurea and short bleomycin treatment in S. pombe. Here I also describe a study performed with our collaborators from Ben-Gurion University of Negev and Duke University. The G1/S transcriptional network in distant yeast species is regulated by homologous proteins, but varies considerably in size. In budding yeast Swi4 and Mbp1 DNA binding components recognize specific SCB and MCB DNA motifs in G1/S target promoters. However, in distantly related yeast species only MCB motif and one transcription factor are present. We establish that Swi4 is the likely ancestral DNA binding domain and a MCB-like motif the likely DNA binding sequence, and the SCB motif representing an optimised sequence for Swi4 binding. Deregulation of G1/S transcription is found in all cancer types. I describe an approach to investigate dependencies of fission yeast with deregulated G1/S transcription as a model of cancer development.

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