Regulation of Transcription by RNA Polymerase II and Cyclin-dependent Kinases (Cdks)

RNA polymerase II (RNAPII) directs transcription of protein coding genes and this process consists of several stages including initiation, elongation and termination. Emerging studies show that the regulation of RNAPII elongation is a highly controlled step of transcription and gene expression, and its disruption can lead to the development of cancer. RNAPII contains a C-terminal domain (CTD) with repeats of heptapeptide YSPTSPS, where individual serines get phosphorylated. Several cyclin-dependent kinases (Cdks) regulate the phosphorylation status of the CTD and the patterns of phosphorylation direct actions of RNAPII during the transcriptional cycle.

Maintenance of genome stability by Cdk12

Cdk12 is a major kinase of the CTD of RNAPII. We found that this virtually unstudied Cdk maintains genome stability via the regulation of transcription of key DNA damage response genes including BRCA1, ATR, ATM, FANCD2 and FANCI - pointing this kinase to be a novel tumor suppressor and a potential drug target. Consistently, comprehensive genomic analyses of patient samples revealed Cdk12 to be among the most often somatically mutated gene in high-grade serous ovarian cancer (HGSOC), the most lethal form of ovarian cancer.

Role of transcriptional Cdks in the onset and development of ovarian and other cancers

Although emerging studies show that aberrant transcriptional regulation leads to tumorigenesis, very little is known about the molecular regulation of Cdk12-dependent transcription and its role in the onset and maintenance of HGSOC and other cancers. To address these hypotheses, we use ovarian cancer-based human cell line models and analyses of HGSOC patient samples to study Cdk12 including individual HGSOC-related mutations of Cdk12. In combination with biochemical, proteomics (mass-spec) and genome-wide techniques (e.g. RNA-seq, expression arrays) in human cancer cell lines, the goal of my lab is to attain an initial molecular understanding of Cdk12-dependent transcription. In a longer term perspective, we envisage this knowledge to eventually lead to the development of novel therapeutic approaches for HGSOC and other Cdk12-dependent cancers.

Main Areas of Research