Synchronicity: policing multiple aspects of gene expression by Ctk1: Figure 1.

Abstract

Transcription and translation are coordinated events in all organisms. In prokaryotes, the process that couples these two events is clear: The ribosome begins translation of the nascent mRNA while the DNA template is still being transcribed. Indeed, cotranscriptional protein synthesis underlies key regulatory mechanisms in bacteria, including attenuation, the mechanism that regulates RNA polymerase processivity in response to ribosome movement along the mRNA. But how is transcription coordinated with translation in eukaryotic organisms, where mRNA is synthesized in the nucleus and protein synthesis occurs in the cytoplasm? Although these two events are spatially distinct, separated by the nuclear envelope, efficient control of gene expression necessarily requires that transcription and translation be regulated in a coordinated manner. As an example, dFOXO-mediated transcriptional activation produces both an inhibitor of cap-dependent translation, eukaryotic translation initiation factor 4E (eIF4E)-BP, and a form of the insulin receptor mRNA that is translated by a cap-independent mechanism (Marr et al. 2007). In addition, translation requires a fully and accurately processed mRNA, and has mechanisms to help sense that appropriate processing has occurred. In the absence of physical coupling of transcription and translation, how are these two processes coordinated in eukaryotes? In this issue of Genes & Development, Rother and Straser (2007) report that the Ctk1 kinase, a key enzyme that facilitates passage of RNA polymerase II (Pol II) through specific stages of the transcription cycle, is also found in the cytoplasm associated with ribosomes actively engaged in protein synthesis (Fig. 1). Their work defines a physiological role for Ctk1 in translation by showing that cellular depletion of Ctk1 decreases total protein synthesis as well as the fidelity of translation elongation. These effects are likely to be a direct effect of Ctk1, since they identified the small ribosomal subunit protein rpS2 as the specific target of the kinase. Moreover, site-directed replacement of rpS2 Ser238, which they identified as the target of Ctk1, results in the same translational defects as depletion of Ctk1. Thus, Rother and Straser (2007) propose that Ctk1 piggybacks with either the mRNP particle or with the pre-40S ribosomal subunit to transit the nuclear envelope to regulate protein synthesis in the cytoplasm. Ctk1 was first identified as a subunit of the yeast CTDK-I complex that catalyzes phosphorylation of the Pol II C-terminal domain (CTD) (Sterner et al. 1995), a reiterated heptapeptide sequence (Tyr1–Ser2–Pro3– Thr4–Ser5–Pro6–Ser7) present at the C terminus of Rpb1 (Kobor and Greenblatt 2002). The CTD couples Pol II transcription with RNA processing, apparently forming a platform for the association and exchange of transcription and RNA processing factors (Hirose and Manley 2000; Orphanides and Reinberg 2002; Proudfoot et al. 2002; Bentley 2005; Meinhart et al. 2005). These factors include the 5 -capping enzymes, the splicing machinery, the 3 -end processing complex, and the transcription export complex (TREX) that facilitates mRNA translocation to the cytoplasm. Progression of Pol II through the transcription cycle is accompanied by changes in the phosphorylation status of the CTD. Pol II is recruited to the promoter in an unphosphorylated form (Pol IIA) that becomes extensively phosphorylated at Ser2 and Ser5 during different stages of the transcription cycle. Differential CTD phosphorylation promotes the exchange of initiation and elongation factors at promoter clearance (Pokholok et al. 2002) and the exchange of elongation and 3 -end processing factors at termination (Kim et al. 2004). CTD phosphorylation is catalyzed by C-type cyclindependent kinases (Prelich 2002). The first of these complexes to be identified is Kin28–Ccl1, which functions as a subcomplex of the general transcription factor TFIIH. Kin28 catalyzes Ser5 phosphorylation coincident with transcription initiation and as a prerequisite for capping (Hengartner et al. 1998; Rodriguez et al. 2000). The second complex, CTDK-I, is composed of three subunits, the Ctk1 kinase, Ctk2 cyclin, and Ctk3 accessory protein that forms a regulatory complex with Ctk2 (Sterner et al. 1995; Hautbergue and Goguel 2001). CTDK-I catalyzes Ser2 phosphorylation during elongation, coinciCorresponding author. E-MAIL kinzytg@umdnj.edu; FAX (732) 235-5223. Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1564807.