- Regulation of eukaryotic transcription
- Role of Cdk9, Cdk12 and Cdk13 in regulation of gene expression
- Role of transcription cycle-related Cdks in maintenance of genome stability
- Transcription cycle-related Cdks in human disease
- Role of Cdks in phosphorylation of the C-terminal domain of RNA polymerase II and in the regulation of gene expression
- Control of DNA damage response and genome stability via regulation of expression of DNA damage response genes
Content of research
RNA polymerase II (RNAPII) directs transcription of protein coding genes and this process consists of several stages including preinitiation complex formation, productive elongation and termination. This transcription cycle is tightly linked to co-transcriptional maturation of nascent transcripts including pre-mRNA splicing and polyadenylation. RNAPII contains an unstructured C-terminal domain (CTD) with repeats of evolutionarily conserved heptapeptide YSPTSPS, where individual serines get phosphorylated. Several cyclin-dependent kinases (Cdks) regulate the phosphorylation status of the CTD and subsequent binding of transcription and pre-mRNA processing factors. Thus, the patterns of phosphorylation of the CTD direct actions of RNAPII during transcriptional cycle and co-transcriptional processing of nascent transcripts. Moreover, CTD was also functionally linked to DNA damage response and maintenance of genome stability via regulation of transcription, mRNA processing and recombination. Thus, CTD and its posttranslational modifications, associated proteins and modifying enzymes are emerging as new players in cellular response to DNA damage. Our recent work led to the identification of the Cyclin K/Cdk12 complex that phosphorylates serine 2 in the CTD of RNAPII and directs expression of several crucial DNA damage response genes including BRCA1, ATR or FANCI. In my lab we apply a combination of biochemical, proteomics and genome-wide techniques to determine the molecular mechanism that regulates the expression of Cdk12-dependent genes with a focus on DNA damage response genes. The ultimate goal of our research is to uncover how the CycK/Cdk12 complex and the CTD of RNAPII contribute to the maintenance of genome stability, and how disruption of their functions lead to the onset of a malignant state.