title: Pause, play, repeat: CDKs push RNAP II's buttons.
abstract: Cyclin-dependent kinases (CDKs) play a central role in governing eukaryotic cell division. It is becoming clear that the transcription cycle of RNA polymerase II (RNAP II) is also regulated by CDKs; in metazoans, the cell cycle and transcriptional CDK networks even share an upstream activating kinase, which is itself a CDK. From recent chemical-genetic analyses we know that CDKs and their substrates control events both early in transcription (the transition from initiation to elongation) and late (3' end formation and transcription termination). Moreover, mutual dependence on CDK activity might couple the "beginning" and "end" of the cycle, to ensure the fidelity of mRNA maturation and the efficient recycling of RNAP II from sites of termination to the transcription start site (TSS). As is the case for CDKs involved in cell cycle regulation, different transcriptional CDKs act in defined sequence on multiple substrates. These phosphorylations are likely to influence gene expression by several mechanisms, including direct, allosteric effects on the transcription machinery, co-transcriptional recruitment of proteins needed for mRNA-capping, splicing and 3' end maturation, dependent on multisite phosphorylation of the RNAP II C-terminal domain (CTD) and, perhaps, direct regulation of RNA-processing or histone-modifying machinery. Here we review these recent advances, and preview the emerging challenges for transcription-cycle research.
authors.affiliation: Department of Structural and Chemical Biology; Icahn School of Medicine at Mount Sinai; New York, NY USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Sansó
authors.forename: Robert P
authors.initials: RP
authors.lastname: Fisher
mesh_terms: D000818:Animals; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D012319:RNA Polymerase II / Q000737:chemistry / Q000378:metabolism*; D012326:RNA Splicing; D013728:Terminator Regions, Genetic; D051758:Transcription Factor TFIIH / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D015003:Yeasts / Q000378:metabolism
chemical_list: D051758:Transcription Factor TFIIH; D042925:Positive Transcriptional Elongation Factor B; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II
keywords: RNA polymerase II; RNA-processing; TFIIH; chemical genetics; cyclin-dependent kinase; positive transcription elongation factor b; promoter-proximal pausing; termination; transcription