? DESCRIPTION (provided by applicant): The cyclin-dependent kinase 12 (CDK12) gene is among the most frequent spontaneously mutated genes in high-grade serous ovarian cancers, the most lethal gynecological malignancy. As we have shown, these mutations disrupt the function of the kinase. Additionally, CDK12 often show loss of copy number in ovarian tumors. Taken together, these findings suggest that CDK12 is often disabled in ovarian cancer. Unlike other CDKs, CDK12 does not regulate cell cycle progression. Instead, CDK12 regulates the expression of a subset of human genes, including BRCA1 such that disabling CDK12 reduces the levels of BRCA1, which facilitates homologous recombination (HR) repair. Consistent with a decrease in BRCA1, disabling CDK12 in ovarian cancer cell lines disrupts HR, sensitizes cells to agents that induce lesions repaired by HR, and sensitizes cells to poly(ADP-ribose) polymerase (PARP) inhibitors, which are selectively toxic to cells with disabled HR. It remains unclear, however, whether CDK12 mutations or reduced CDK12 levels affect the responses of human ovarian tumors to PARP inhibitors that are currently in Phase 3 clinical trials. Additionally, our understanding of the regulation and biochemical roles of CDK12 remains incomplete. Recent studies showed that CDK12 phosphorylates Ser2 in the heptapeptide repeats of the C-terminal domain (CTD) of RBP1, the largest subunit of RNA polymerase II (RNAPII). This phosphorylation regulates multiple aspects of transcription by recruiting chromatin modifiers and remodelers, and facilitating mRNA splicing, 3' end cleavage, and polyadenylation. Despite this progress, however, it is not currently known how CDK12 is regulated, nor do we know whether CDK12 regulates gene expression solely by phosphorylation of Ser2 in the CTD of RBP1 or by phosphorylating other substrates. In this application we will to examine how CDK12 is regulated (Aim 1), evaluate how CDK12 regulates pre-mRNA splicing (Aim 2), and determine whether the expression levels of CDK12 pathway components correlates with patient outcomes in women with high-grade serous ovarian cancer treated with platinum-based therapy (Aim 3). Impact and Relevance: Collectively, these studies are relevant because they will 1) provide novel mechanistic insights into the regulation and biochemical roles of CDK12, a protein kinase with major impacts on tumor biology but whose mechanisms of action remain obscure; and 2) determine whether the CDK12 pathway is associated with responses to standard-of-care therapy and novel therapies for ovarian cancer.
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