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A nitrogen source-regulated microprotein confers an alternative mechanism of G1/S transcriptional activation in budding yeast

ABSTRACT: Commitment to cell division at the end of G1 phase, termed Start in the budding yeast Saccharomyces cerevisiae, is strongly influenced by nutrient availability. To identify new dominant activators of Start that might operate under different nutrient conditions, we screened a genome-wide ORF overexpression library for genes that bypass a Start arrest caused by absence of the G1 cyclin Cln3 and the transcriptional activator Bck2. We recovered a hypothetical gene YLR053c, renamed NRS1 for Nitrogen-Responsive Start regulator 1, which encodes a poorly characterized 108 amino acid microprotein. Endogenous Nrs1 was nuclear-localized, restricted to poor nitrogen conditions, induced upon mTORC1 inhibition, and cell cycle-regulated with a peak at Start. NRS1 interacted genetically with SWI4 and SWI6, which encode subunits of the main G1/S transcription factor complex SBF. Correspondingly, Nrs1 physically interacted with Swi4 and Swi6 and was localized to G1/S promoter DNA. Nrs1 exhibited inherent transactivation activity and fusion of Nrs1 to the SBF inhibitor Whi5 was sufficient to suppress other Start defects. Nrs1 appears to be a recently evolved microprotein that rewires the G1/S transcriptional machinery under poor nutrient conditions.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE179366 | GEO | 2021/08/25

REPOSITORIES: GEO

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NRS1, a nitrogen source-regulated microprotein, confers an alternative mechanism of G1/S transcriptional activation in budding yeast

Project description:Commitment to cell division at the end of G1 phase, termed Start in the budding yeast Saccharomyces cerevisiae, is strongly influenced by nutrient availability. To identify newdominant activators of Start that might operate under different nutrient conditions, we screened a genome-wide ORF overexpression library for genes that bypass a Start arrest caused by absence of the G1 cyclin Cln3 and the transcriptional activator Bck2. We recovered a hypothetical gene YLR053c, renamed NRS1 for Nitrogen-responsive Start Regulator 1, which encodes a poorly characterized 108 amino acid microprotein. Endogenous NRS1 was nuclear-localized, restricted to poor nitrogen conditions, induced upon mTORC1 inhibition, and cell cycle-regulated with a peak at Start. NRS1 interacted genetically with SWI4 and SWI6, which encode the master G1/S transcription factor complex SBF. Correspondingly, NRS1 physically interacted with Swi4 and Swi6 and was localized to G1/S promoter DNA. NRS1 exhibited inherent transactivation activity and fusion of NRS1 to the SBF inhibitor Whi5 was sufficient to suppress other Start defects. NRS1 appears to be a recently evolved microprotein that rewires the G1/S transcriptional machinery under poor nutrient conditions.

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Differential regulation of SBF and MBF target genes by genotoxic stress occurs via Rad53-dependent inactivation of the MBF correpressor Nrm1

Project description: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 corepressor, Nrm1. Using genome-wide expression analysis, we show that genotoxic stress during S phase specifically induces MBF-regulated genes via direct phosphorylation of Nrm1 by Rad53, the effector checkpoint kinase, and prevents its binding to MBF target promoters. Interestingly, some previously defined targets of SBF, including Swe1, are activated by replication stress. Swe1 undergoes a transcription factor exchange leading to its repression by Nrm1/MBF, which renders it sensitive to derepression by the S phase checkpoint. 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. Modified Loop Time-series design, time points at 0, 30, 45, 60 and 75 minutes. Conditions are untreated (UT), methyl methane sulfonate (MMS-0.033%), camptothecin (CPT-50uM), and hydroxyurea (HU-0.2M)

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