title: JNK1 phosphorylation of Cdt1 inhibits recruitment of HBO1 histone acetylase and blocks replication licensing in response to stress.
abstract: In response to environmental stresses, cells activate stress-response genes and inhibit DNA replication. HBO1 histone acetylase is a coactivator both for AP-1 transcription factors responding to stress-activated JNK kinases and also for the Cdt1 licensing factor that ensures that DNA is replicated exactly once per cell cycle. In response to nongenotoxic stress, JNK phosphorylates Jun, an AP-1 transcription factor, leading to increased recruitment of HBO1 and increased transcription of target genes. In addition, JNK phosphorylates Cdt1 on threonine 29, leading to rapid dissociation of HBO1 from replication origins, thereby blocking initiation of DNA replication. Upon relief of stress, HBO1 reassociates with replication origins. Thus, regulated and reciprocal recruitment of the HBO1 coactivator to target genes and replication origins via JNK-mediated phosphorylation of the recruiting transcription and replication licensing factors coordinates the transcriptional and DNA replication response to cellular stress.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Benoit
authors.initials: B
authors.lastname: Miotto
authors.forename: Kevin
authors.initials: K
authors.lastname: Struhl
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004261:DNA Replication; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D013912:Threonine / Q000737:chemistry / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D013912:Threonine; D051548:Histone Acetyltransferases; C496553:KAT7 protein, human; D048055:Mitogen-Activated Protein Kinase 8