CDK7 is a cyclin-dependent kinase shown to be not easily classified. CDK7 is both a CDK-activating kinase (CAK) and a component of the general transcription factor TFIIH.
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An intricate network of cyclin-dependent kinases (CDKs) are organized in a pathway to ensure that each cell accurately replicates its DNA and segregate it equally between the two daughter cells[1]. One CDK–the CDK7 complex–cannot be so easily classified. CDK7 is both a CDK-activating kinase (CAK), which phosphorylates cell-cycle CDKs within the activation segment (T-loop), and a component of the general transcription factor TFIIH, which phosphorylates the C-terminal domain (CTD) of the largest subunit of Pol II[2]. A proposed mode of CDK7 inhibition is the phosphorylation of cyclin H by CDK7 itself[3] or by another kinase[4].
In order to be active, most CDKs require not only a cyclin partner but also phosphorylation at one particular site, which corresponds to Thr161 in human CDK1, and which is located within the so-called T-loop of kinase subdomain VIII[5][6]. CDKl, CDK2 and CDK4 all require T-loop phosphorylation for maximum activity[7][8].
An entirely new perspective on CDK7 function was opened when CDK7 was identified as a subunit of transcription factor IIH (TFIIH) and shown to phosphorylate the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII)[9]. TFIIH is a multiprotein complex required not only for class II transcription but also for nucleotide-excision repair[10]. Its associated CTD-kinase activity is considered important for the promoter-clearance step of transcription, but the precise structural consequences of the phosphorylation of the CTD remain the subject of debate[11]. Cyclin H and MAT1 are also present in TFIIH[12], and it is not known what, if anything, distinguishes the TFIIH-associated form of CDK7 from the quantitatively predominant free form. Whether CDK7 really displays dual-substrate specificity remains to be further explored, but there is no question that the CDK7-cyclin H-MAT1 complex is able to phosphorylate both the T-loop of CDKs and the YSPTSPS (single-letter code for amino acids) repeats of the RNAPII CTD in vitro.
It has been demonstrated that TFIIH is a rate-limiting factor for HIV transcription in unactivated T-cells by using a combination of in vivo ChIP experiments and cell-free transcription studies[13]. The ability of NF-κB to rapidly recruit TFIIH during HIV activation in T-cells is an unexpected discovery; however, there are several precedents in the literature of cellular genes that are activated through the recruitment of TFIIH. In an early and influential paper[14], demonstrated that type I activators such as Sp1 and CTF, which were able to support initiation but were unable to support efficient elongation, were also unable to bind TFIIH. By contrast, type II activators such as VP16, p53 and E2F1, which supported both initiation and elongation, were able to bind to TFIIH. In one of the most thoroughly characterized transcription systems[15], have studied the temporal order of recruitment of transcription factors during the activation of the major histocompatibility class II (MHC II) DRA gene by IFN-gamma. Following induction of the CIITA transcription factor by IFN-gamma, there was recruitment of both CDK7 and CDK9 causing RNAP CTD phosphorylation and elongation. Finally, Nissen and Yamamoto (2000)[16] in their studies of the activation of the IL-8 and ICAM-1 promoters observed enhanced CDK7 recruitment and RNAP II CTD phosphorylation in response to NF-κB activation by TNF.
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