title: DNA replication stress differentially regulates G1/S genes via Rad53-dependent inactivation of Nrm1.
abstract: 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 co-repressor, Nrm1. Using genome-wide expression analysis of cells treated with methyl methane sulfonate (MMS), hydroxyurea (HU) or camptothecin (CPT), we show that genotoxic stress during S phase specifically induces MBF-regulated genes. This occurs via direct phosphorylation of Nrm1 by Rad53, the effector checkpoint kinase, which prevents its binding to MBF target promoters. 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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Travesa
authors.forename: Dwight
authors.initials: D
authors.lastname: Kuo
authors.forename: Robertus A M
authors.initials: RA
authors.lastname: de Bruin
authors.forename: Tatyana I
authors.initials: TI
authors.lastname: Kalashnikova
authors.forename: Marisela
authors.initials: M
authors.lastname: Guaderrama
authors.forename: Kevin
authors.initials: K
authors.lastname: Thai
authors.forename: Aaron
authors.initials: A
authors.lastname: Aslanian
authors.forename: Marcus B
authors.initials: MB
authors.lastname: Smolka
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
authors.forename: Curt
authors.initials: C
authors.lastname: Wittenberg
mesh_terms: D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000235:genetics*; D004261:DNA Replication; D016193:G1 Phase / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal; D006918:Hydroxyurea / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D009153:Mutagens; C513403:Nrm1 protein, S cerevisiae; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D008741:Methyl Methanesulfonate; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae; D006918:Hydroxyurea; D002166:Camptothecin