Abstract AS21: Ovarian carcinoma CDK12 mutations misregulate DNA repair genes via deficient formation and function of the Cdk12/CycK complex

Abstract

Abstract The Cdk12/CycK complex promotes gene expression by phosphorylating the C-terminal domain of RNA polymerase II. In previous work we found that CDK12/CycK complex maintains genomic stability via regulation of expression of several key DNA damage response genes such as BRCA1, ATR, FANCD2 or FANCI. CDK12 is among only nine genes with recurrent somatic mutations in high-grade serous ovarian carcinoma. However, the influence of these mutations on the Cdk12/CycK complex and their link to cancerogenesis remain ill-defined. Here, we show that most mutations interfere with the Cdk12/CycK complex formation, rendering the kinase inactive. By examining the mutations within the Cdk12/CycK structure, we find that they likely provoke structural rearrangements detrimental to Cdk12 activation. Our mRNA expression analysis of the patient samples containing the CDK12 mutations identifies coordinated down-regulation of key DNA damage response genes. Accordingly, we observed that the mutant Cdk12 proteins fail to promote the repair of DNA double strand breaks via homologous recombination. Together, we provide the molecular basis of how mutated CDK12 ceases to function in ovarian carcinoma. We propose that CDK12 is a tumor suppressor of which the loss-of-function mutations may elicit defects in multiple DNA repair pathways, leading to genomic instability that underlies the genesis of the cancer.. Citation Format: Kingsley M. Ekumi, Hana Paculova,Vendula Pospichalova, Christian A. Bosken,Vitezslav Bryja, Matthias Geyer, Dalibor Blazek, Matjaz Barboric. Ovarian carcinoma CDK12 mutations misregulate DNA repair genes via deficient formation and function of the Cdk12/CycK complex [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS21.