# CCNH

## Overview
CCNH, or Cyclin H, is a gene that encodes the protein cyclin H, which is a regulatory component of the CDK-activating kinase (CAK) complex. This complex is crucial for cell cycle progression and transcription regulation through its role in phosphorylating the CDK enzymes. Cyclin H is not directly involved in the cell cycle control but rather plays a significant role in transcription regulation by forming complexes with transcriptional CDKs. The protein is characterized by a cyclin box domain essential for its function and interaction with CDK7, another component of the CAK complex. Abnormalities in the expression or function of cyclin H are associated with various cancers, making it a potential target for therapeutic interventions (Zhang2013Low; Patel2010Functional).

## Structure
Cyclin H (CCNH) is characterized by a distinct structural configuration that differentiates it from other cyclins involved in cell cycle control. Notably, Cyclin H lacks the N-CBF recruitment site found in cell cycle cyclins such as cyclin A, B, D, and E. This absence is attributed to structural variations including a shorter a4 helix and a differently positioned loop between the a4 and a5 helices. These structural features significantly remodel the area around R63, a residue equivalent to W217 in cyclin A, suggesting that Cyclin H utilizes alternative surfaces within its cyclin box fold (CBF) for mediating protein-protein interactions (Wood2018Structural).

The cyclin box domain (CBD) in Cyclin H, typically found at the N-terminal half of cyclins, is crucial for binding and activating cyclin-dependent kinases (CDKs). This domain consists of approximately 100 amino acids arranged in five alpha-helices, which is a common feature among cyclins, although specific structural details can vary significantly across different family members (Quandt2019Atypical).

These structural insights indicate that Cyclin H plays a specialized role in transcription regulation by forming complexes with transcriptional CDKs, rather than participating directly in cell cycle control (Wood2018Structural).

## Function
Cyclin H (CCNH) is a regulatory subunit of the Cdk-activating kinase (CAK) complex, which includes cyclin-dependent kinase 7 (CDK7) and MAT1. This complex is essential for the activation of CDK enzymes that regulate the cell cycle by phosphorylating key proteins. CCNH is crucial for the kinase activity of CDK7, influencing the phosphorylation of the carboxyl-terminal domain of RNA polymerase II, a process vital for transcription initiation and the recruitment of chromatin-modifying factors (Patel2010Functional).

In addition to its role in cell cycle regulation, CCNH is involved in transcription as part of the general transcription factor IIH (TFIIH) core. Within this complex, it assists in the phosphorylation of transcription factors, thereby influencing gene expression by either enhancing or repressing their activity. The activity of the CAK complex varies depending on the cell type, indicating a cell-specific requirement for its function (Patel2010Functional).

Abnormal expression of CCNH and CDK7 is linked to various malignancies, highlighting their importance not only in normal cell cycle progression but also in the development of cancer (Zhang2013Low). This underscores the dual role of CCNH in maintaining normal cellular functions and its potential involvement in pathological conditions when dysregulated.

## Clinical Significance
Mutations and alterations in the expression of the CCNH gene, which encodes Cyclin H, have been implicated in various cancers, highlighting its clinical significance. In breast cancer, lower mRNA expression levels of CCNH are observed in tumor tissues compared to normal breast tissues, and higher expression levels are associated with better overall survival outcomes (Liu2022Cyclin). This suggests that CCNH could serve as a potential prognostic biomarker and therapeutic target in breast cancer management.

Furthermore, the CCNH gene is involved in the susceptibility to differentiated thyroid cancer (DTC). The single nucleotide polymorphism (SNP) rs2230641 in the CCNH gene is significantly associated with an increased risk of DTC, particularly in the follicular subset of this cancer (SANTOS2013The). This association underscores the potential of CCNH as a marker for assessing cancer risk and tailoring preventive strategies in individuals at higher genetic risk.

Additionally, the interaction of Cyclin H with other proteins, such as CDK7, influences cancer cell migration and invasion, particularly in breast cancer. Alterations in this interaction can affect the stability of other proteins like CtBP2, which is involved in cancer progression (Wang2013Interaction). This interaction highlights the broader implications of CCNH in cancer biology, beyond its role in cell cycle regulation.

## Interactions
CCNH, also known as Cyclin H, forms a complex with CDK7 (cyclin-dependent kinase 7) and MAT1 (ménage à trois 1), which is part of the CDK-activating kinase (CAK) essential for cell cycle control and transcription. This complex activates CDK2, crucial for cell cycle progression. Beyond its role in the CAK complex, Cyclin H interacts with other proteins, influencing various cellular processes, including cancer progression and metastasis.

One significant interaction is with C-terminal binding protein 2 (CtBP2), where CCNH/CDK7 stabilizes CtBP2 by protecting it from proteasomal degradation. This stabilization occurs through the disruption of the interaction between CtBP2 and HIPK2, a kinase that promotes CtBP2 degradation. The presence of CCNH/CDK7 inhibits CtBP2 phosphorylation, enhancing its dimerization and function as a transcriptional repressor, which is crucial for the migratory and invasive capabilities of cancer cells, particularly in breast cancer and esophageal squamous cell carcinoma (ESCC) (Wang2013Interaction; Zhang2015Interaction).

These interactions suggest that targeting the CCNH/CDK7-CtBP2 axis could be a potential therapeutic strategy in treating metastatic cancers, highlighting the importance of CCNH in both cell cycle regulation and cancer progression (Wang2013Interaction; Zhang2015Interaction).


## References


[1. (Zhang2013Low) Jianguo Zhang, Xiaojing Yang, Yuchan Wang, Hui Shi, Chengqi Guan, Li Yao, Xianting Huang, Zongmei Ding, Yuejiao Huang, Huijie Wang, and Chun Cheng. Low expression of cyclinh and cyclin-dependent kinase 7 can decrease the proliferation of human esophageal squamous cell carcinoma. Digestive Diseases and Sciences, 58(7):2028–2037, March 2013. URL: http://dx.doi.org/10.1007/s10620-013-2597-x, doi:10.1007/s10620-013-2597-x. (21 citations) 10.1007/s10620-013-2597-x](https://doi.org/10.1007/s10620-013-2597-x)

[2. (Zhang2015Interaction) Jianguo Zhang, Junya Zhu, Lei Yang, Chengqi Guan, Runzhou Ni, Yuchan Wang, Lili Ji, and Ye Tian. Interaction with ccnh/cdk7 facilitates ctbp2 promoting esophageal squamous cell carcinoma (escc) metastasis via upregulating epithelial-mesenchymal transition (emt) progression. Tumor Biology, 36(9):6701–6714, March 2015. URL: http://dx.doi.org/10.1007/s13277-015-3354-x, doi:10.1007/s13277-015-3354-x. (27 citations) 10.1007/s13277-015-3354-x](https://doi.org/10.1007/s13277-015-3354-x)

[3. (SANTOS2013The) LUÍS S. SANTOS, BRUNO C. GOMES, RITA GOUVEIA, SUSANA N. SILVA, ANA P. AZEVEDO, VANESSA CAMACHO, ISABEL MANITA, OCTÁVIA M. GIL, TERESA C. FERREIRA, EDWARD LIMBERT, JOSÉ RUEFF, and JORGE F. GASPAR. The role of ccnh val270ala (rs2230641) and other nucleotide excision repair polymorphisms in individual susceptibility to well-differentiated thyroid cancer. Oncology Reports, 30(5):2458–2466, August 2013. URL: http://dx.doi.org/10.3892/or.2013.2702, doi:10.3892/or.2013.2702. (22 citations) 10.3892/or.2013.2702](https://doi.org/10.3892/or.2013.2702)

[4. (Quandt2019Atypical) Eva Quandt, Mariana P. C. Ribeiro, and Josep Clotet. Atypical cyclins: the extended family portrait. Cellular and Molecular Life Sciences, 77(2):231–242, August 2019. URL: http://dx.doi.org/10.1007/s00018-019-03262-7, doi:10.1007/s00018-019-03262-7. (41 citations) 10.1007/s00018-019-03262-7](https://doi.org/10.1007/s00018-019-03262-7)

[5. (Liu2022Cyclin) Nian-Qiu Liu, Wei-Han Cao, Xing Wang, Junyao Chen, and Jianyun Nie. Cyclin genes as potential novel prognostic biomarkers and therapeutic targets in breast cancer. Oncology Letters, September 2022. URL: http://dx.doi.org/10.3892/ol.2022.13494, doi:10.3892/ol.2022.13494. (4 citations) 10.3892/ol.2022.13494](https://doi.org/10.3892/ol.2022.13494)

[6. (Wang2013Interaction) Yuchan Wang, Fang Liu, Feng Mao, Qinlei Hang, Xiaodong Huang, Song He, Yingying Wang, Chun Cheng, Huijie Wang, Guangfei Xu, Tianyi Zhang, and Aiguo Shen. Interaction with cyclin h/cyclin-dependent kinase 7 (ccnh/cdk7) stabilizes c-terminal binding protein 2 (ctbp2) and promotes cancer cell migration. Journal of Biological Chemistry, 288(13):9028–9034, March 2013. URL: http://dx.doi.org/10.1074/jbc.m112.432005, doi:10.1074/jbc.m112.432005. (73 citations) 10.1074/jbc.m112.432005](https://doi.org/10.1074/jbc.m112.432005)

[7. (Patel2010Functional) Shetal A. Patel and M. Celeste Simon. Functional analysis of the cdk7·cyclin h·mat1 complex in mouse embryonic stem cells and embryos. Journal of Biological Chemistry, 285(20):15587–15598, May 2010. URL: http://dx.doi.org/10.1074/jbc.m109.081687, doi:10.1074/jbc.m109.081687. (23 citations) 10.1074/jbc.m109.081687](https://doi.org/10.1074/jbc.m109.081687)

[8. (Wood2018Structural) Daniel J. Wood and Jane A. Endicott. Structural insights into the functional diversity of the cdk–cyclin family. Open Biology, September 2018. URL: http://dx.doi.org/10.1098/rsob.180112, doi:10.1098/rsob.180112. (158 citations) 10.1098/rsob.180112](https://doi.org/10.1098/rsob.180112)