Cyclin-dependent kinase 7 is an enzyme that in humans is encoded by the CDK7 gene. The monomers of CDK are not active and must be combined with the corresponding cyclins (Cyclins) to form active isoforms. Dimer complexes play a regulatory role in catalyzing the phosphorylation of corresponding substrates, driving the various processes of the cell cycle, completing DNA synthesis and mitosis in sequence, causing cell growth and proliferation. The human genome has been found to encode 21 CDKs and more than 15 Cyclins. According to their functions, CDKs can be divided into two categories: CDKs that control the cell cycle and CDKs that are transcribed by cells. Among them, CDK1/2/4/6 is mainly related to the replication of genetic information in cell cycle regulation, while CDK 7/8/9/10 is mainly related to the transcription mechanism of intracellular genetic information.

Figure 1. Protein structure of CDK7.

Introductions

CDK7 has the function of activating kinases. The CDK activating kinase (CAK) complex composed of CDK7, CyclinH, and MAT1 can phosphorylate a variety of CDK (1, 2, 4, 6) kinases involved in cell cycle regulation. For example, CDK2, which drives the cell cycle into the S phase, and CDK1, which drives the cell cycle into mitosis, dominate the start, progress, and end of the cell cycle. On the other hand, CDK7 is mainly involved in the regulation of the transcription process, and it can phosphorylate Ser residues at positions 5 and 7 of the carboxyl terminal domain (CTD) of the large subunit of RNA polymerase II, which promotes the initiation of transcription. More and more studies show that CDK7 is closely related to the occurrence of tumors such as leukemia, triple-negative breast cancer, small cell lung cancer, gastric cancer and neuroblastoma. Therefore, CDK7 is considered as a potential drug target for the treatment of malignant tumors.

Structural features of CDK7

CDK7 has a classic protein kinase fold, including the N-terminal (13-96 residues) and C-terminal (97-311 residues) kinase leaves. The N-terminal kinase leaf is mainly composed of β-sheet and an α-helix, and the C-terminal kinase leaf is mainly composed of α-helix. There is a gap between residues 44 to 55 of the N-terminal kinase leaf, which corresponds to the connection between the β3 fold and the α helix. In addition, residues 1 to 12 and 312 to 346 contain a possible nuclear localization sequence. The ATP-binding site is located between the N-terminal and C-terminal kinase leaves and is highly conserved. The N-terminal kinase domain's αC helix contains NRTALRE-like sequences, which correspond to other CDK family subtypes that bind to cyclin-like PSTAIRE sequences.

Biological function and mechanism of CDK7

As an important member of the CDK family, CDK7 participates in the formation of the CDK7-CyclinH binary complex or the CDK7-CyclinH-MAT1 ternary complex, which is activated by phosphorylation to generate active CAK, which is used in the cell cycle, transcription and DNA damage repair Play an important role. CDK7-CyclinH-MAT1 is also a subunit of the universal transcription factor TFIIH. TFIIH is composed of ten subunits, of which 7 subunits (p62, p52, p44, p34, XPD, XPB and TTDA) form the core structure. Combined with the core structure of TFIIH after interacting with XPD. The transcription process of RNA can be divided into three stages: initiation, extension and termination. In the initial stage of transcription, the DNA helicase in TFIIH acts on the DNA fragment of the core promoter, and CDK7 can phosphorylate Ser residues at positions 5 and 7 of CTD of RNA polymerase II, which promotes promoter clearance and further promotes transcription Start. The activation of CDK7 can promote the departure of the transcription factor TFIHI and the recruitment of the nucleoside analog DRB-sensitive induction factor (DSIF) and negative elongation factor (NELF), resulting in transcriptional termination near the promoter region. CDK7 activates CDK9 by phosphorylating the CDK9 T-loop region. The activated CDK9 phosphorylates the RNA polymerase II CTD Ser residue at 2 and also phosphorylates the RD subunit of NELF and the SPT5 subunit of DSIF. NELF is gone, allowing transcription to be extended. CDK7 plays a seemingly contradictory function in the establishment and release of transcription termination. In fact, this short pause before the recruitment of transcription elongation factor and activation of CDK9 is to better promote transcription.

Reference:

1. Fisher RP; et al. A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell. 1994, 78 (4): 713–24