# The Less Known Cyclins--Uncovered
## 5 Cyclin H  
Cyclin H is a cell cycle protein encoded by the CCNH gene. Its main function is the activation of Cdk7. The interaction between Cdk7 and cyclin H is stabilized by phosphorylation of Cdk7 in its activation segment. However, the complex may also be stabilized by Matl [45; 46]. Cyclin H together with Cdk7 and Matl forms the structure of Cdk activating kinase (CAK), which is a member of the Cdk family and acts as a positive regulator of Cdk1, Cdk2, Cdk4 and Cdk6 through threonine phosphorylation [47].  
In normal cells, cyclin H in the CAK complex plays an important role in the regulation of transcription as a module of the TFIIH transcription factor. As the component of TFIIH, CAK phosphorylates series 5 and 7 of the carboxyl terminus domain of RNA polymerase II, allowing promoter clearance and enabling the transcription initiation. This provides a direct connection between the cell cycle machinery and the regulation of transcription. The CAK complex may also directly phosphorylate transcription factors to regulate gene expression [23; 48]. Moreover, the transcription process regulated by the CAK complex affects the differentiation of embryonic cells (ES). [PERSON] et al., 2010 [49] showed that the loss of the function of cyclin H in ES induces the process of their differentiation as the cyclin phosphorylates the Spt5 negative transcription factor leading to its activation. In turn, Spt5 regulates RNA processing and pause transcription [49].  
A high level of cyclin H expression is associated with gastrointestinal stromal tumors (GIST). [PERSON] et al., 2010 [50] based on the cyclin H mRNA level, showed 10-fold increased transcription of cyclin H in GIST compared to normal tissue. These results suggest the important role of cyclin H in the pathogenesis of GIST. The authors showed cyclin H overexpression in 24% of tumors, which was also correlated with the risk of malignancy. In addition, for patients with tumor recurrences and/or metastases, increased expression of cyclin H was associated with decreased disease-specific survival. The level of expression of cyclin H in GIST varied between high and very high risk concerning specific mortality for this type of cancer, thanks to which it can be used as a prognostic marker [50].  
Moreover, the regulation of cyclin H correlates with lower proliferation in diffuse large B-cell lymphoma (DLBCL). [PERSON] et al. 2008 [51] observed a reduction or lack of expression of cyclin H in 14.5% of DLBCL cases. Simultaneously, reduced expression of cyclin H correlated with lower expression of the cyclins B1, D3 and E, and Ki-67 proliferation marker. Downregulation of cyclin H was significantly associated with poor overall survival, both in the one-dimensional and multifactor analysis with the international predictive index. The authors demonstrated an independent prognostic value of the expression of cyclin H in DLBCL and propose its use as a prognostic marker [51].  
Overexpression of cyclin H is also observed in breast cancer. Based on the studies conducted by [PERSON] et al., 2010 [49] it was found that the mRNA levels of cyclin H and Mat1 required for Cdk7 activity are increased in breast cancer, which indicates an increase in CAK complex activity [52].  
Inhibition of CDK7 activity seems like reasonable anticancer strategy. The several molecules show good efficiency against cancer cell lines. Two clinical trials conducting CDK7 inhibitors are currently ongoing: Modular Study to Evaluate CT7001 Alone in Cancer Patients with Advanced Malignancies (NCT03363893) and A Study of SY-1365 in Adult Patients with Advanced Solid Tumors (NCT03134638).