Nrm1 is a bistable switch connecting cell cycle progression to transcriptional control
Entry into the cell cycle requires activation of G1 cyclin-dependent kinases (CDKs) and the initiation of the G1/S transcriptional program. Unregulated transcription of this gene expression program can lead to genomic instability and aneuploidy. In fission yeast, the MBF complex is the key transcription factor that drives early cell-cycle gene expression. MBF-dependent transcription is triggered in metaphase and is suppressed at the end of S phase by a robust feedback mechanism involving the cyclin Cig2 and the co-repressors Nrm1 and Yox1. Under replicative stress, Yox1 is phosphorylated to release its repressive activity; however, the precise mechanism activating MBF in an unperturbed cell cycle remains unclear. Here, we identify Nrm1 as the primary target of the cell cycle machinery in regulating MBF activity through a two-step control mechanism. We demonstrate that CDK1-mediated phosphorylation of Nrm1 initiates its release, along with Yox1, from chromatin in metaphase. This mechanism overlaps with the irreversible degradation of unphosphorylated Nrm1 (which originates from de novo synthesis or by dephosphorylation of pre-existing Nrm1 during anaphase), preventing its re-association with MBF until the end of the following S phase. These parallel mechanisms, which sense cell cycle status, create a regulated window in which MBF-dependent transcription is relieved from repression, supporting orderly cell cycle progression. Overall design: Study the role of nrm1 phosphorylation in cell cycle transcription