title: Stress-stimulated mitogen-activated protein kinases control the stability and activity of the Cdt1 DNA replication licensing factor.
abstract: DNA replication is tightly coordinated both with cell cycle cues and with responses to extracellular signals to maintain genome stability. We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2. Mutations that block normal cell cycle-regulated MAP kinase-mediated phosphorylation interfere with rapid Cdt1 reaccumulation at the end of S phase. Phosphomimetic mutations recapitulate the stabilizing effects of Cdt1 phosphorylation but also reduce the ability of Cdt1 to support origin licensing. Two other CRL4(Cdt2) targets, the cyclin-dependent kinase (CDK) inhibitor p21 and the methyltransferase PR-Set7/Set8, are similarly stabilized by MAP kinase activity. These findings support a model in which MAP kinase activity in G(2) promotes reaccumulation of a low-activity Cdt1 isoform after replication is complete.
authors.affiliation: Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7260, USA.
authors.forename: Srikripa
authors.initials: S
authors.lastname: Chandrasekaran
authors.forename: Ting Xu
authors.initials: TX
authors.lastname: Tan
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Hall
authors.forename: Jeanette Gowen
authors.initials: JG
authors.lastname: Cook
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016195:G2 Phase; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D009997:Osmotic Pressure; D010766:Phosphorylation; D018741:Replication Origin; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C429530:DTL protein, human; D009687:Nuclear Proteins; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; C540312:SETD7 protein, human; D044767:Ubiquitin-Protein Ligases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases