Studies have shown that CDK12 regulates DNA repair genes by inhibiting intron polyadenylation
December 17, 2018 Source: Ministry of Science and Technology
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];On November 28th, researchers at the Massachusetts Institute of Technology published an article entitled "CDK12 regulates DNA repair genes by suppressing intronic polyadenylation" in the journal Nature, reporting on the function of CDK12 and its application prospects in tumor detection and treatment.
Mutations that attenuate homologous recombination (HR)-mediated DNA repair can promote tumorigenesis and sensitize cells to chemotherapeutic drugs that cause replication fork collapse. This phenotype is called "BRCAness". . BRCAness tumors are derived from functional deletion mutations in 22 genes. Of these genes, only CDK12 acts directly on the HR repair pathway. CDK12 phosphorylates the RNA polymerase II C-terminal domain heptapeptide repeat of serine 2, which regulates transcriptional elongation, splicing, cleavage and polyadenylation. Whole genome expression studies indicated that deletion of CDK12 relatively inhibited the expression of several HR genes, thereby inhibiting HR repair. This phenomenon suggests that the mutational state of CDK12 can predict the sensitivity of BRCAness targeted therapy, such as the sensitivity prediction of PARP1 inhibitors. CDK12 inhibitors can promote tumors with HR function to be sensitive to these therapies. Despite the growing interest in clinical research by researchers, the mechanism by which CDK12 regulates the HR gene remains unclear. In the present study, the researchers found that CDK12 can comprehensively inhibit polyadenylation of introns in mouse embryonic stem cells, enabling them to produce full-length gene products. Many HR genes contain more intron polyadenylation sites than other expressed genes, and these sites are particularly susceptible to deletion of CDK12. The cumulative effect of these sites is associated with increased sensitivity of HR gene expression to CDK12 deletion, and this mechanism is conserved in human tumors containing CDK12 loss-of-function mutations. This study clarifies the function of CDK12 and is expected to be applied to the development of chemotherapy targets and tumor biomarkers. (Excerpt from Nature, Published: 28 November 2018)
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