EMBO paper for the De Bruin Group

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.

Abstract

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 Clb/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.