In this proposal we will explore the role of cyclin-dependent kinase 12 (CDK12) in E2F-retinoblastoma (Rb) pathway-dependent transcription and early cell cycle progression. This little studied transcriptional CDK was found among only nine significantly mutated genes in high grade serous ovarian carcinoma (HGSOC) (2). All the mutations compromised the kinase activity of CDK12 on its only known substrate, the C-terminal domain (CTD) of RNA Polymerase II (RNAPII).In previous studies we found that CDK12 maintains genome stability via optimal transcription of key homologous recombination (HR) repair pathway genes including BRCA1, FANCD2 and ATM, identifying this kinase as a novel tumor suppressor candidate in HGSOC and a potential drug target . Our preliminary results show that CDK12 is expressed in a cell cycle-dependent manner and a proportion of CDK12-dependent transcripts is regulated via the E2F-Rb pathway.
Furthermore, our experiments and analyses of published screens in HGSOC patients and ovarian cancer cell lines suggest that transcription of E2F-RB-linked oncogene CycE, a protein deregulated in up to 50% of HGSOC, is CDK12-dependent. Our data also indicate that CDK12 is unlikely to regulate the transcription of E2F-dependent transcripts via the phosphorylation of the CTD. Altogether, these findings suggest an oncogenic function of CDK12 in CycE-dependent ovarian cancers and provide important insight into two putative and different roles (suppressor and oncogenic) CDK12 may play in the onset and maintenance of various HGSOC. Considering important role of E2F-Rb pathway in cellular proliferation and its common deregulation occurance in cancer we believe that elucidating the molecular mechanism CDK12 play in the pathway is of high importance and might underline future clinical interest in CDK12.

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