Abstract 2167 Modeling CDK12 and CDK13 Loss-of-Function to Investigate Their Roles in Alternative Polyadenylation

CDK12 and CDK13 are cyclin-dependent kinases that phosphorylate Serine 2 of the RNA polymerase II C-terminal domain (RNAPII CTD) during transcription, along with CDK9. Serine 2 phosphorylation (pSer2) signals for release of RNAPII from the promoter proximal pause and is maintained throughout elongation. Additionally, both CDK12 and CDK13 are mutated in various cancers. Cells carrying loss-of-function (LOF) mutations in CDK12 phenocopy BRCA1/2 LOF, resulting in the loss of DNA homologous recombination, which promotes tumorigenesis due to increased genomic instability.