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Nrm1 is a bistable switch connecting cell cycle progression to transcriptional control

ABSTRACT: 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.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE287772 | GEO | 2025/07/23

REPOSITORIES: GEO

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Project description:In the budding yeast Saccharomyces cerevisiae, transcription factors (TFs) regulate the periodic expression of many genes during the cell cycle, including gene products required for progression through cell-cycle events. Experimental evidence coupled with quantitative models suggest that a network of interconnected TFs is capable of regulating periodic genes over the cell cycle. Importantly, these dynamical models were built on transcriptomics data and assumed that TF protein levels and activity are directly correlated with mRNA abundance. To ask whether TF transcripts match protein expression levels as cells progress through the cell cycle, we applied a multiplexed targeted mass spectrometry approach (parallel reaction monitoring) on synchronized populations of cells. We found that protein expression of many TFs and cell-cycle regulators closely followed their respective mRNA transcript dynamics in cycling wild-type cells. Discordant mRNA/protein expression dynamics were also observed for a subset of cell-cycle TFs and for proteins targeted for degradation by E3 ubiquitin ligase complexes such as SCF (Skp1/Cul1/F-box) and APC/C (anaphase-promoting complex/cyclosome). We further profiled mutant cells lacking B-type cyclin/CDK activity (clb1-6), where oscillations in ubiquitin ligase activity, cyclin/CDKs, and cell-cycle progression are halted. We found that a number of proteins were no longer periodically degraded in clb1-6 mutants compared to wild type, highlighting the importance of post-transcriptional regulation. Finally, the TF complexes responsible for activating G1/S transcription (SBF and MBF) were more constitutively expressed at the protein level than their periodic mRNA expression levels in both wild-type and mutant cells. This comprehensive investigation of cell-cycle regulators reveals that multiple layers of regulation (transcription, protein stability, and proteasome targeting) affect protein expression dynamics during the cell cycle.

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Nrm1 is a bistable switch connecting cell cycle progression to transcriptional control

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