Linking DNA replication checkpoint to MBF cell-cycle transcription reveals a distinct class of G1/S genes.

ABSTRACT

Reprogramming gene expression is crucial for DNA replication stress response. We used quantitative proteomics to establish how the transcriptional response results in changes in protein levels. We found that expression of G1/S cell-cycle targets are strongly up-regulated upon replication stress, and show that MBF, but not SBF genes, are up-regulated via Rad53-dependent inactivation of the MBF co-repressor Nrm1. A subset of G1/S genes was found to undergo an SBF-to-MBF switch at the G1/S transition, enabling replication stress-induced transcription of genes targeted by SBF during G1. This subset of G1/S genes is characterized by an overlapping Swi4/Mbp1-binding site and is enriched for genes that cause a cell cycle and/or growth defect when overexpressed. Analysis of the prototypical switch gene TOS4 (Target Of SBF 4) reveals its role as a checkpoint effector supporting the importance of this distinct class of G1/S genes for the DNA replication checkpoint response. Our results reveal that replication stress induces expression of G1/S genes via the Rad53-MBF pathway and that an SBF-to-MBF switch characterizes a new class of genes that can be induced by replication stress.