CDK12 regulates DNA repair genes by suppressing intronic polyadenylation.

Abstract

Mutations that attenuate homologous recombination (HR) repair promote tumorigenesis and sensitize cells to chemotherapeutics that cause replication fork collapse, a phenotype known as “BRCAness.”1 BRCAness tumors arise from loss-of-function mutations in 22 genes.1 Of these genes, all but one (Cdk12) directly function in the HR repair pathway.1 Cdk12 phosphorylates Serine 2 of the RNA Polymerase II (RNAPII) C-terminal domain (CTD) heptapeptide repeat,2–7 a modification that regulates transcription elongation, splicing, and cleavage/polyadenylation.8,9 Genome-wide expression studies suggest that Cdk12 depletion abrogates the expression of several HR genes relatively specifically, blunting HR repair.3–7,10,11 This observation suggests that Cdk12 mutational status may predict sensitivity to targeted treatments against BRCAness, such as Parp1 inhibitors, and that Cdk12 inhibitors may induce sensitization of HR-competent tumors to these treatments.6,7,10,11 Despite growing clinical interest, the mechanism by which Cdk12 regulates HR genes remains unknown. Here we find that Cdk12 globally suppresses intronic polyadenylation events, enabling the production of full-length gene products. Many HR genes harbor more intronic polyadenylation sites than other expressed genes, and these sites are particularly sensitive to Cdk12 loss. The cumulative effect of these sites accounts for the enhanced sensitivity of HR gene expression to Cdk12 loss, and we find that this mechanism is conserved in human tumors harboring Cdk12 loss-of-function mutations. This work clarifies the function of CDK12 and underscores its potential both as a chemotherapeutic target and as a tumor biomarker.