CDK12 regulates DNA repair genes by suppressing intronic polyadenylation

Article

关键词: EMBRYONIC STEM-CELLS;    POLYMERASE-II CTD;    MESSENGER-RNA;    HOMOLOGOUS RECOMBINATION;    SYNTHETIC LETHALITY;    TRANSCRIPTION;    EXPRESSION;    INHIBITION;    P53;    PHOSPHORYLATION;   

DOI  :  10.1038/s41586-018-0758-y

来源: SCIE

【 摘 要 】

Mutations that attenuate homologous recombination (HR)mediated repair promote tumorigenesis and sensitize cells to chemotherapeutics that cause replication fork collapse, a phenotype known as 'BRCAness'(1). BRCAness tumours arise from loss-of-function mutations in 22 genes(1). Of these genes, all but one (CDK12) function directly in the HR repair pathway(1). CDK12 phosphorylates serine 2 of the RNA polymerase II C-terminal domain heptapeptide repeat(2-7), a modification that regulates transcription elongation, splicing, and cleavage and polyadenylation(8,9). Genome-wide expression studies suggest that depletion of CDK12 abrogates the expression of several HR genes relatively specifically, thereby blunting HR repair(3-7,10,11). This observation suggests that the mutational status of CDK12 may predict sensitivity to targeted treatments against BRCAness, such as PARP1 inhibitors, and that CDK12 inhibitors may induce sensitization of HR-competent tumours to these treatments(6,7,10,11). Despite growing clinical interest, the mechanism by which CDK12 regulates HR genes remains unknown. Here we show that CDK12 globally suppresses intronic polyadenylation events in mouse embryonic stem cells, enabling the production of full-length gene products. Many HR genes harbour more intronic polyadenylation sites than other expressed genes, and these sites are particularly sensitive to loss of CDK12. 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 tumours that contain loss-of-function CDK12 mutations. This work clarifies the function of CDK12 and underscores its potential both as a chemotherapeutic target and as a tumour biomarker.

【 授权许可】

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