CDK13/CDC2L5 interacts with L-type cyclins and regulates alternative splicing
Due to the strong sequence homology it has been suggested that CDC2L5 and CDK12 belong to a high molecular weight subfamily of CDC2 family with PITAI/VRE motifs [F. Marques, J.L. Moreau, G. Peaucellier, J.C. Lozano, P. Schatt, A. Picard, I. Callebaut, E. Perret, A.M. Geneviere, A new subfamily of high molecular mass CDC2-related kinases with PITAI/VRE motifs, Biochem. Biophys. Res. Commun. 279 (2000) 832-837]. Recently, we reported that CDK12 interacts with L-type cyclins and is involved in alternative splicing regulation [H.-H. Chen, Y.-C. Wang, M.-J. Fann, Identification and characterization of the CDK12/Cyclin L1 complex involved in alternative splicing regulation, Mol. Cel. Biol. 26 (2006) 2736-2745]. Here, we provide evidence that CDC2L5 also interacts with L-type cyclins and thus rename it as cyclin-dependent kinase 13 (CDK13). The kinase domain of CDK13 is sufficient to bind the cyclin domains of L-type cyclins. Moreover, CDK13 and L-type cyclins modulate each other's subcellular localization. When CDK13 and an E1a minigene reporter construct were over-expressed in HEK293T cells, CDK13 alters the splicing pattern of E1a transcripts in a dose-dependent manner. Similar to effects of CDK12, effects of CDK13 on splicing pattern are counteracted by SF2/ASF and SC35. These findings strengthen CDK12 and CDK13 as a subfamily of cyclin-dependent kinases that regulate alternative splicing.
Available from: PubMed Central
- "These heterodimers are both implicated in the control of RNA-pol-II-mediated transcription [42–44]. CDK12 and CDK13 may also associate with L-type cyclins and take part in the regulation of alternative RNA splicing [45, 46]. "
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ABSTRACT: The CDK9-related pathway is an important regulator of mammalian cell biology and is also involved in the replication cycle of several viruses, including the human immunodeficiency virus type 1. CDK9 is present in two isoforms termed CDK9-42 and CDK9-55 that bind noncovalently type T cyclins and cyclin K. This association forms a heterodimer, where CDK9 carries the enzymatic site and the cyclin partner functions as a regulatory subunit. This heterodimer is the main component of the positive transcription elongation factor b, which stabilizes RNA elongation via phosphorylation of the RNA pol II carboxyl terminal domain. Abnormal activities in the CDK9-related pathway were observed in human malignancies and cardiac hypertrophies. Thus, the elucidation of the CDK9 pathway deregulations may provide useful insights into the pathogenesis and progression of human malignancies, cardiac hypertrophy, AIDS and other viral-related maladies. These studies may lead to the improvement of kinase inhibitors for the treatment of the previously mentioned pathological conditions. This review describes the CDK9-related pathway deregulations in malignancies and the development of kinase inhibitors in cancer therapy, which can be classified into three categories: antagonists that block the ATP binding site of the catalytic domain, allosteric inhibitors, and small molecules that disrupt protein-protein interactions.
06/2013; 2013(9):305371. DOI:10.1155/2013/305371
Available from: Jiri Kohoutek
- "Cdk12 was shown to phosphorylate CTD of RNAPII, in vitro . Based on the interaction of Cdk12 and Cdk13 with overexpressed Cyclin L (CycL), CycL was reported to be their regulatory subunit, and the same studies suggested a role in the regulation of alternative splicing [28,29]. However, recent studies have reported that the endogenous Drosophila Cdk12 and human Cdk12 and Cdk13 do not associate with CycL, but rather with CycK [5,6]. "
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ABSTRACT: The cyclin-dependent kinases (Cdks) regulate many cellular processes, including the cell cycle, neuronal development, transcription, and posttranscriptional processing. To perform their functions, Cdks bind to specific cyclin subunits to form a functional and active cyclin/Cdk complex. This review is focused on Cyclin K, which was originally considered an alternative subunit of Cdk9, and on its newly identified partners, Cdk12 and Cdk13. We briefly summarize research devoted to each of these proteins. We also discuss the proteins' functions in the regulation of gene expression via the phosphorylation of serine 2 in the C-terminal domain of RNA polymerase II, contributions to the maintenance of genome stability, and roles in the onset of human disease and embryo development.
Cell Division 04/2012; 7(article 12):12. DOI:10.1186/1747-1028-7-12 · 3.53 Impact Factor
Available from: April L MacKellar
- "In terms of the cyclin partner of CDK12, our lab found that endogenous dCDK12 associates with cyclinK, a Ctk2-like cyclin that has been previously characterized as an alternative partner for CDK9 . These findings are inconsistent with previous reports that CDK12 and CDK13 interact with the L class cyclins  ; thus, whether cyclinK is the cyclin partner of human CDK12 and CDK13 remains to be determined. As of this paper, other than our initial characterization, there have been no published studies of CDK12 and CDK13 in the context of transcription and transcriptional elongation, thus much remains to be learned about these kinases. "
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ABSTRACT: Eukaryotic RNA polymerase II (RNAPII) not only synthesizes mRNA but also coordinates transcription-related processes via its unique C-terminal repeat domain (CTD). The CTD is an RNAPII-specific protein segment consisting of repeating heptads with the consensus sequence Y(1)S(2)P(3)T(4)S(5)P(6)S(7) that has been shown to be extensively post-transcriptionally modified in a coordinated, but complicated, manner. Recent discoveries of new modifications, kinases, and binding proteins have challenged previously established paradigms. In this paper, we examine results and implications of recent studies related to modifications of the CTD and the respective enzymes; we also survey characterizations of new CTD-binding proteins and their associated processes and new information regarding known CTD-binding proteins. Finally, we bring into focus new results that identify two additional CTD-associated processes: nucleocytoplasmic transport of mRNA and DNA damage and repair.
10/2011; 2011(1):623718. DOI:10.4061/2011/623718
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