All eukaryotes: before turning off G1-S transcription, please check your DNA

Abstract

The DNA replication and DNA damage checkpoints are required for the efficient response to genotoxic stress, which is critical for genome stability and cell survival. The DNA replication and damage checkpoints delay progression into mitosis, and at the same time induce the transcription of genes that promote repair of cellular lesions including stabilization of stalled replication forks and induction of DNA repair functions. The elucidation of the mechanism by which the DNA replication checkpoint activates transcription of G1/S genes is provided by our recent study reported in the August issue of Proceedings of the National Academy of Sciences. We show that, in response to stimulation of the DNA replication checkpoint, activation of G1-S transcription is established by inactivation, via phosphorylation by the checkpoint protein kinases, of the MBF-associated transcriptional corepressor Nrm1. This regulation is critical for the survival of cells responding to genotoxic stress. This provides a simple but elegant mechanism by which checkpoint activation can override the regular periodic transcriptional program by directly regulating a cell cycle dependent transcriptional repressor. We discuss the likely conservation of this regulatory pathway in yeast and man.