Pereira Fraga Caetano, CM; (2013) G1/S Cell Cycle Regulated Transcription and Genome Stability. Doctoral thesis , UCL (University College London).

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Abstract

Initiation of a new round of cell proliferation in eukaryotic cells is associated with coordinated transcriptional activation of genes during the G1-to-S transition. In the fission yeast Schizosaccharomyces pombe, genes involved in DNA replication are tightly regulated by the transcription factor MBF during G1/S. Recently, the MBF-associated corepressors Nrm1p and Yox1p were shown to have a non-redundant role in a negative feedback loop mechanism to repress MBF-dependent transcription outside of G1. Activation of the DNA replication checkpoint results in persistent expression of MBF-dependent genes. Here we show that in response to DNA replication stress both Yox1p and Nrm1p dissociate from MBF at promoters, leading to de-repression of MBF targets. Inactivation of Yox1p is an essential part of the checkpoint response. Cds1p checkpoint protein kinase-dependent phosphorylation of Yox1p promotes its dissociation from the MBF transcription factor. We establish that phosphorylation of Yox1p at Ser114 and Thr115 is required for maximal checkpoint-dependent activation of the G1/S cell-cycle transcriptional programme. G1/S transcription includes many genes required for replication and recovery of stalled replication forks. Although persistent expression of the G1/S transcriptional programme is an important part of the DNA replication checkpoint response we show that constitutive expression of the same group of genes outside of G1 and S is detrimental for cells undergoing normal cell cycle progression. Cells abrogated for nrm1+ and yox1+ experience increased genomic instability. We demonstrate that a delicate balance exists between levels of DNA replication initiation factors and CDK activity in these cells. Disruption of this balance induces further genome instability, a hallmark of cancer development.

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