Characterization of cyclin-dependent kinases 12 and 11 (CDK12 and CDK11) in gene expression and tumorigenesis

Cdk12 is transcriptional cyclin-dependent kinase (Cdk) found mutated in various cancers. In previous studies we found that Cdk12 maintains genome stability via optimal transcription of key homologous recombination repair pathway genes including BRCA1. Apart from the C-terminal domain of RNA Polymerase II other cellular substrates for both kinases are not known. In this research we propose using a screen in cells carrying an analog sensitive mutant of CDK12 to discover its novel cellular substrates. The substrates and their roles in normal and cancerous cells will be characterized by various techniques of molecular biology and biochemistry.
CDK11 is ubiquitously expressed in all tissues and the CDK11 null mouse is lethal at an early stage of development indicating an important role for Cdk11 in the adult as well as during development. CDK11 is believed to play a role in RNAPII-directed transcription and co-transcriptional mRNA-processing, particularly alternative splicing and 3´end processing. However, its genome-wide function in regulating the human transcriptome is unknown. Notably, several recent studies identified CDK11 as a candidate essential gene for growth of several cancers therefore, understanding the molecular mechanism(s) of CDK11-dependent gene expression would be also of significant clinical interest.In this research we will use various techniques of molecular biology and biochemistry to characterize genome-wide role of CDK11 in regulation of gene expression.
The applicant may focus on one of these areas
Characterization of cyclin-dependent kinase 12 (CDK12) substrates and their roles in regulation of transcription and tumorigenesis
Functions of cyclin-dependent kinase 11 (CDK11) in regulation of gene expression

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Applicants who wish to pursue a degree at the CEITEC PhD program must hold the equivalent of a Master’s degree (MSc) in similar field (four- or five-year undergraduate degree). The application can be submitted before obtaining the Master’s degree, however, the applicant should obtain the degree within five months after the application deadline.