Title: DNA replication stress differentially regulates G1/S genes via Rad53-dependent inactivation of Nrm1.
Authors: Travesa, A; Kuo, D; de Bruin, RA; Kalashnikova, TI; Guaderrama, M; Thai, K;, Aslanian, A; Smolka, MB; Yates, JR 3rd; Ideker, T; Wittenberg, C.
MBF and SBF transcription factors regulate a large family of coordinately expressed G1/S genes required for early cell-cycle functions including DNA replication and repair. SBF is inactivated upon S-phase entry by C1b/CDK whereas MBF targets are repressed by the co-repressor, Nrm1. Using genome-wide expression analysis of cells treated with methyl methane sulfonate (MMS), hydroxyurea (HU) or camptothecin (CPT), we show that genotoxic stress during S phase specifically induces MBF-regulated genes. This occurs via direct phosphorylation of Nrm1 by Rad53, the effector checkpoint kinase, which prevents its binding to MBF target promoters. We conclude that MBF-regulated genes are distinguished from SBF-regulated genes by their sensitivity to activation by the S-phase checkpoint, thereby, providing an effective mechanism for enhancing DNA replication and repair and promoting genome stability.