Delegate Talk: Genomic and Genetic Analyses of the Transcriptional Regulation of G1/S Genes by Genotoxic Stress

Anna Travesa, Curt Wittenerg, Dwight Kuo, Robert A.M. de Bruin, Trey Ideker and Curt Wittenberg

Genomic and Genetic Analyses of the Transcriptional Regulation of G1/S Genes by Genotoxic Stress

 Anna Travesa^1,4, Dwight Kuo², Robert A.M. de Bruin³, Trey Ideker², and Curt Wittenberg¹

1. Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA  92037
2. Departments of Bioengineering and Medicine,University of California, San Diego, La Jolla, CA  92093
3. MRC Laboratory for Molecular Cell Biology, University College London, London, WC1E 6BT United Kingdom
4. Current address: Department of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093

 The G1/S-phase transition is critical for cell cycle progression. In the budding yeast Saccharomyces cerevisiae, this transition is driven by a wave of gene expression that is under the control of the cell cycle-regulated transcription factors SBF and MBF. SBF mainly targets genes involved in timing, morphogenesis and spindle pole body duplication, whereas MBF regulates many genes involved in DNA replication and repair. During S phase, the DNA replication checkpoint detects DNA replication stress and generates a global response that includes the transcriptional induction of genes involved in DNA replication and repair. We find that MBF-dependent transcription is induced in response to DNA damage and replication stress. This induction takes place via direct phosphorylation of the transcriptional corepressor Nrm1 by the checkpoint kinase Rad53, which renders it unable to bind to promoters and repress transcription as cells progress into S phase. Using genome-wide RNA microarrays, we have shown that approximately a third of the G1/S specific genes are induced in response to DNA damage and replication stress, and that this induction is largely dependent upon Rad53. Moreover, almost 80 % of those genes are regulated by Nrm1, highlighting the general relevance of the Rad53-dependent inactivation of Nrm1 by the checkpoint. This checkpoint regulation of G1/S gene expression is conserved in the distantly related fungi, Schizosaccharomyces pombe, and also in eukaryotic cells. By inducing many genes involved in DNA replication and repair, this newly characterized pathway enhances genomic stability in the face of a broad range of genotoxic stresses.