CRK7, also known as CDK12, which is a transcription-related cyclin-dependent kinase that phosphorylates serine in the carbon-terminal amino acid of RNA polymerase II and participates in a variety of cellular physiological processes such as DNA damage response, cell proliferation and differentiation, and mRNA splicing and pre-transcriptional mRNA processing, etc. In addition, mutations in the genes encoding the CDK12 will lead to abnormal regulation of a variety of cellular processes and increase in genetic instability, which may promote tumorigenesis and development. In the human genome, the closest homologous gene to CDK12 is CDK13. CDK13, also known as CDC2L5 (cell division cycle 2-like protein kinase 5), contains a kinase domain with a high sequence identity to the CDK12 kinase domain. Similar to CDK12, CDK13 can phosphorylate RNA polⅡCTD, and can also form an independent complex with cyclin K, but the target of CDK13 is not in RNA polⅡCTD Ser2/5. The current research on CDK13 is far less than CDK12, and its function and mechanism of action are not clear. Because the gene coding sequences of CDK13 and CDK12 are similar, it is also believed that these two kinases may have similar physiological functions.
CDK is an important kinase that regulates various cellular processes. It can be divided into cell cycle-related CDKs (such as CDK1 / 2/4/6) and transcription-related CDKs (such as CDK7/8/9/11/12/13). Cell cycle-related CDKs directly affect cell proliferation by regulating the progress of the body's cell cycle at various stages; transcription-related CDKs mainly regulate genes by phosphorylating RNA binding protein 1, Rbp1 of the C-terminal domain Transcription. CDK12 is a transcription-related CDK that can phosphorylate the carboxy terminal domain of RNA polymerase Ⅱ (RNA pol II CTD), which is useful for DNA damage repair (DDR) and mRNA splicing. And cell proliferation and differentiation are critical. Studies have shown that CDK12 gene mutations and overexpression are widespread in a variety of malignant tumors (especially breast cancer), and inhibiting the expression of CDK12 in tumors will help people understand the specific physiological functions of CDK12. At present, related research on CDK12 inhibitors has attracted increasing attention, and such inhibitors have broad prospects as part of tumor-targeted drug treatments.
Moradian et al. Applied mass spectrometry to determine several factors that make up the spliceosome, including splicing factor 2; SF2 / alternative splicing factor; ASF, splicing component 35; SC35. Subsequent studies have shown that these factors are closely related to CDK12-regulated RNA splicing, but most of them have not been confirmed by intramolecular splicing assays and immunoprecipitation reactions. Related studies have shown that CDK12 is involved in the alternative splicing of axon protein IV and mRNA binding protein HOW during the development of the Drosophila nervous system.
Although the specific function and mechanism of CDK12 in cells is not completely clear, it is clear that it plays a very important role in DDR. Studies have shown that inhibiting CDK12 reduces the expression of key factors that maintain gene stability such as BRCA1, ATR, FANCI, and FANCD2, inhibits homologous recombination (HR) transcriptional activity, reduces the efficiency of DNA double-strand break repair, and blocks the DDR process; Inactivation of the CDK12 / cyclin K complex results in increased endogenous DNA damage on the one hand, and impairs the ability of cells to effectively perform homologous recombination, which in turn leads to DDR disorders. Although the specific mechanism of CDK12 in DDR is not completely clear, it is certain that CDK12 has an irreplaceable role in maintaining genome stability and HR transcriptional activity and promoting DNA damage repair. The accumulation of DDR damage and DNA damage is one of the typical characteristics of cancer. The above results show that CDK12 deficiency is closely related to tumor development.