Cyclin-dependent kinases and transcription initiation

Cyclin-dependent kinases (CDKs) are a large family of heterodimeric serine/threonine kinases that belong to the CMGC group of eukaryotic protein kinases. Apart from CDKs, this group includes mitogen-activated kinases (MAPKs), glycogen synthase kinases (GSKs) and CDK-like kinases (CLKs) (reviewed by Champion et al., 2004; Hanks, 2003; Manning et al., 2002;). By definition, CDKs require the binding of cyclins for their activity (although additional proteins bind and activate CDKs in the absence of cyclins (reviewed by Nebreda, 2006).
Cyclins function as the regulatory subunit of the cyclin/CDK complex whereas CDKs act as the catalytic subunit. CDKs are well-established regulators of the eukaryotic cell cycle (Nigg, 1995; Morgan, 1997; Nurse, 2002) and have profound effects on nuclear structure and function. Activation of the mitotic CDKA leads to disassembly of many nuclear structures, including the nucleolus and many other structures involved in gene expression. Other CDKs appear to have roles in specific aspects of nuclear function, including gene transcription, pre-mRNA processing, translation and DNA damage responses.

Gene transcription is a highly complex and multi-step process involving chromatin modification, assembly of transcription initiation complexes on gene promoters, pre-mRNA transcript initiation, elongation and termination. The first step in this process is the formation of the pre-initiation complex  (PIC) on the promoter of the gene, which is established in a step-by-step process (Buratowski et al., 1989; Ranish and Hahn, 1996). Assembly of the transcriptional apparatus for transcription initiation begins with the recruitment of general transcription factors (GTFs) to gene promoters. TFIID is first recruited and binds to the DNA promoter, followed by TFIIA and TFIIB and then RNA Polymerase II, in association to TFIIF. PIC is finally established with the loading of TFIIE and TFIIH. Even though PIC is sufficient to drive transcription in vitro, it is unable to respond to activators. This observation suggested the existence of a bridge complex that responds to activator molecules and signals the PIC to initiate transcription. This complex was first isolated in yeast and termed “Mediator” (Flanagan et al., 1991; Kim et al., 1994). The Mediator complex is conserved from yeast to plants and mammals and is important in mediating the activation of RNA Polymerase II (PolII), leading to promoter clearance and transcript elongation (Boube et al., 2002; Max et al., 2007).

PolII is the enzyme responsible for pre-mRNA transcription in eukaryotic cells. It is composed of two large subunits and a collection of smaller subunits. The unique characteristic of PolII is the presence of a domain at the C-terminus of its large subunit, comprised of tandem repeats of the consensus sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser (Corden, 1990) and termed the C-terminal domain (CTD). The number of this hepta-peptide repeat varies across eukaryotes, from 26-27 in yeast, 42 repeats in Caenorhabditis elegans, 44 in Drosophila melanogaster to 25 in Arabidopsis thaliana.

Reversible phosphorylation of the CTD is an important regulatory mechanism for transcription initiation, pre-mRNA processing and transcription termination, since the phosphorylation status of the CTD dictates its binding specificity to the respective regulatory factors (Hirose and Manley, 2000). CTD is phosphorylated by the TFIIH and positive transcription elongation b (P-TEFb) transcriptions factors. In mammals, the catalytic subunit of TFIIH is the cyclin-dependent kinase 7 (CDK7)/CyclinH whereas for P-TEFb is the CDK9/CycT (Serizawa et al., 1995; Marshall et al., 1996). Further to the involvement of CDK7- and CDK9- containing complexes in the regulation of gene transcription, new CDK/Cyclin complexes have been found to contribute to the complex regulatory network of gene transcription, pre-mRNA processing and mRNA translation.


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