# CDK7

## Overview
CDK7 is a gene that encodes the protein cyclin-dependent kinase 7, a serine/threonine kinase integral to cell cycle regulation and transcriptional control. As a member of the cyclin-dependent kinase family, CDK7 forms part of the CDK-activating kinase (CAK) complex, which includes cyclin H and the assembly factor MAT1. This complex is essential for the activation of other CDKs, thereby facilitating cell cycle progression. Additionally, CDK7 is a component of the general transcription factor TFIIH, where it phosphorylates the C-terminal domain of RNA polymerase II, a critical step in transcription initiation and elongation. The dual role of CDK7 in cell cycle and transcription underscores its importance in cellular proliferation and its potential as a therapeutic target in cancer (Fisher1994A; Nigg1995Cyclin‐dependent; Lolli2005CAK—CyclinDependent).

## Structure
Cyclin-dependent kinase 7 (CDK7) is a serine/threonine kinase that plays a crucial role in cell cycle regulation and transcription. The primary structure of CDK7 includes specific phosphorylation sites, notably at threonine 170 (T170) and serine 164 (S164), which are essential for its activation (Düster2024Structural; Düster2024Structurala). 

The secondary structure of CDK7 consists of an N-terminal lobe primarily composed of β sheets and one α helix, and a C-terminal lobe made up mostly of α helices (Lolli2004The). The tertiary structure involves the kinase domain, which is stabilized by phosphorylation at T170, forming salt bridges with residues R61, R136, and K160, and interacting with Cyclin H and Mat1 (Düster2024Structural; Düster2024Structurala).

In its quaternary structure, CDK7 forms a complex with Cyclin H and Mat1, known as the CDK-activating kinase (CAK) complex. This assembly is crucial for its function and stability, with Mat1 sealing the cleft between CDK7 and Cyclin H, forming a tight ternary assembly (Düster2024Structural; Düster2024Structurala). The dual phosphorylation of the T-loop at S164 and T170 is a key post-translational modification that enhances CDK7's activity towards transcriptional substrates (Düster2024Structural; Düster2024Structurala).

## Function
CDK7, a cyclin-dependent kinase, plays a pivotal role in cell cycle regulation and transcription in healthy human cells. It is a key component of the CDK-activating kinase (CAK) complex, which includes cyclin H and the assembly factor MAT1. This complex is responsible for phosphorylating and activating other CDKs, such as CDK1, CDK2, CDK4, and CDK6, which are essential for cell cycle progression (Fisher1994A; Lolli2005CAK—CyclinDependent). The phosphorylation typically occurs on a conserved threonine residue within the T loop of CDKs, a modification necessary for their full enzymatic activity (Fisher1994A).

CDK7 also functions as part of the general transcription factor TFIIH, where it phosphorylates the C-terminal domain (CTD) of RNA polymerase II. This activity is crucial for the initiation and elongation phases of transcription, highlighting CDK7's dual role in both cell cycle regulation and transcriptional control (Nigg1995Cyclin‐dependent; Lolli2005CAK—CyclinDependent). CDK7's activity is constant throughout the cell cycle but is reduced in quiescent cells, and it is ubiquitously expressed in tumor cells, indicating its potential as a target for cancer therapy (Lolli2005CAK—CyclinDependent).

## Clinical Significance
CDK7 (cyclin-dependent kinase 7) plays a significant role in various cancers due to its involvement in cell cycle regulation and transcription. Alterations in CDK7 expression or function are linked to several cancer types. In breast cancer, particularly estrogen receptor (ER)-positive tumors, CDK7 is often overexpressed, suggesting that these cancers may be sensitive to CDK7 inhibition (Patel2016Expression). High CDK7 expression is also associated with poor prognosis in triple-negative breast cancer (TNBC), where it is considered a potential therapeutic target (Li2017Therapeutic; Wang2015CDK7-Dependent).

CDK7 is frequently deleted in multiple epithelial cancers, including ovarian serous cystadenocarcinoma and prostate adenocarcinoma, leading to reduced mRNA expression in these tumors (Shan2020Systematic). In head and neck squamous-cell cancer (HNSCC), high CDK7 expression correlates with worse outcomes, indicating its potential as a prognostic biomarker (Jagomast2022CDK7).

CDK7 inhibitors, such as THZ1, have shown promise in preclinical models by impairing cell proliferation and inducing apoptosis in various cancers, including breast, ovarian, and head and neck cancers (Shan2020Systematic; Jagomast2022CDK7). These inhibitors are being explored for their potential to enhance the efficacy of existing cancer therapies and overcome drug resistance.

## Interactions
CDK7 interacts with several proteins, forming part of the CDK-activating kinase (CAK) complex alongside cyclin H and MAT1. This complex is crucial for the activation of other cyclin-dependent kinases (CDKs) through phosphorylation, influencing cell cycle progression and transcription (Fisher2005Secrets). CDK7 also associates with the transcription factor IIH (TFIIH) complex, where it phosphorylates the C-terminal domain (CTD) of RNA polymerase II, playing a significant role in transcription initiation (Fisher2005Secrets).

The interaction between CDK7 and CDK2 has been extensively studied. CDK7 phosphorylates CDK2, and structural modeling has shown a semi-stable complex formation between these proteins, characterized by specific electrostatic and van der Waals interactions (Lolli2007Recognition). CDK7's interaction with CDK2 is not dependent on the sequences around phosphorylation sites but rather on structural determinants at remote sites (Lolli2007Recognition).

CDK7 also interacts with CtBP2, a transcriptional corepressor, through its association with cyclin H. This interaction stabilizes CtBP2 by preventing its proteasomal degradation, which is significant in cancer cell migration and metastasis (Wang2013Interaction). The CDK7/Cyclin H/Mat1 complex is further stabilized by dual T-loop phosphorylation, which is essential for its full kinase activity (Düster2024Structural).


## References


[1. (Fisher2005Secrets) Robert P. Fisher. Secrets of a double agent: cdk7 in cell-cycle control and transcription. Journal of Cell Science, 118(22):5171–5180, November 2005. URL: http://dx.doi.org/10.1242/jcs.02718, doi:10.1242/jcs.02718. This article has 400 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.02718)

[2. (Lolli2005CAK—CyclinDependent) Graziano Lolli and Louise N. Johnson. Cak—cyclin-dependent activating kinase: a key kinase in cell cycle control and a target for drugs? Cell Cycle, 4(4):565–570, January 2005. URL: http://dx.doi.org/10.4161/cc.4.4.1607, doi:10.4161/cc.4.4.1607. This article has 139 citations and is from a peer-reviewed journal.](https://doi.org/10.4161/cc.4.4.1607)

[3. (Düster2024Structural) Robert Düster, Kanchan Anand, Sophie C. Binder, Maximilian Schmitz, Karl Gatterdam, Robert P. Fisher, and Matthias Geyer. Structural basis of cdk7 activation by dual t-loop phosphorylation. Nature Communications, August 2024. URL: http://dx.doi.org/10.1038/s41467-024-50891-z, doi:10.1038/s41467-024-50891-z. This article has 0 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-024-50891-z)

[4. (Lolli2004The) Graziano Lolli, Edward D. Lowe, Nick R. Brown, and Louise N. Johnson. The crystal structure of human cdk7 and its protein recognition properties. Structure, 12(11):2067–2079, November 2004. URL: http://dx.doi.org/10.1016/J.STR.2004.08.013, doi:10.1016/j.str.2004.08.013. This article has 160 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/J.STR.2004.08.013)

[5. (Li2017Therapeutic) Bo Li, Triona Ni Chonghaile, Yue Fan, Stephen F. Madden, Rut Klinger, Aisling E. O’Connor, Louise Walsh, Gillian O’Hurley, Girish Mallya Udupi, Jesuchristopher Joseph, Finbarr Tarrant, Emer Conroy, Alexander Gaber, Suet-Feung Chin, Helen A. Bardwell, Elena Provenzano, John Crown, Thierry Dubois, Sabine Linn, Karin Jirstrom, Carlos Caldas, Darran P. O’Connor, and William M. Gallagher. Therapeutic rationale to target highly expressed cdk7 conferring poor outcomes in triple-negative breast cancer. Cancer Research, 77(14):3834–3845, July 2017. URL: http://dx.doi.org/10.1158/0008-5472.can-16-2546, doi:10.1158/0008-5472.can-16-2546. This article has 79 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/0008-5472.can-16-2546)

[6. (Patel2016Expression) Hetal Patel, Rezvan Abduljabbar, Chun-Fui Lai, Manikandan Periyasamy, Alison Harrod, Carolina Gemma, Jennifer H. Steel, Naina Patel, Claudia Busonero, Dena Jerjees, Judit Remenyi, Sally Smith, Jennifer J. Gomm, Luca Magnani, Balázs Győrffy, Louise J. Jones, Frances Fuller-Pace, Sami Shousha, Laki Buluwela, Emad A. Rakha, Ian O. Ellis, R. Charles Coombes, and Simak Ali. Expression of cdk7, cyclin h, and mat1 is elevated in breast cancer and is prognostic in estrogen receptor–positive breast cancer. Clinical Cancer Research, 22(23):5929–5938, November 2016. URL: http://dx.doi.org/10.1158/1078-0432.ccr-15-1104, doi:10.1158/1078-0432.ccr-15-1104. This article has 67 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/1078-0432.ccr-15-1104)

[7. (Wang2015CDK7-Dependent) Yubao Wang, Tinghu Zhang, Nicholas Kwiatkowski, Brian J. Abraham, Tong Ihn Lee, Shaozhen Xie, Haluk Yuzugullu, Thanh Von, Heyuan Li, Ziao Lin, Daniel G. Stover, Elgene Lim, Zhigang C. Wang, J. Dirk Iglehart, Richard A. Young, Nathanael S. Gray, and Jean J. Zhao. Cdk7-dependent transcriptional addiction in triple-negative breast cancer. Cell, 163(1):174–186, September 2015. URL: http://dx.doi.org/10.1016/j.cell.2015.08.063, doi:10.1016/j.cell.2015.08.063. This article has 337 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.cell.2015.08.063)

[8. (Fisher1994A) Robert P. Fisher and David O. Morgan. A novel cyclin associates with m015/cdk7 to form the cdk-activating kinase. Cell, 78(4):713–724, August 1994. URL: http://dx.doi.org/10.1016/0092-8674(94)90535-5, doi:10.1016/0092-8674(94)90535-5. This article has 481 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/0092-8674(94)90535-5)

[9. (Nigg1995Cyclin‐dependent) Erich A. Nigg. Cyclin‐dependent protein kinases: key regulators of the eukaryotic cell cycle. BioEssays, 17(6):471–480, June 1995. URL: http://dx.doi.org/10.1002/bies.950170603, doi:10.1002/bies.950170603. This article has 674 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/bies.950170603)

[10. (Jagomast2022CDK7) Tobias Jagomast, Christian Idel, Luise Klapper, Patrick Kuppler, Anne Offermann, Eva Dreyer, Karl-Ludwig Bruchhage, Julika Ribbat-Idel, and Sven Perner. Cdk7 predicts worse outcome in head and neck squamous-cell cancer. Cancers, 14(3):492, January 2022. URL: http://dx.doi.org/10.3390/cancers14030492, doi:10.3390/cancers14030492. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cancers14030492)

[11. (Lolli2007Recognition) Graziano Lolli and Louise N. Johnson. Recognition of cdk2 by cdk7. Proteins: Structure, Function, and Bioinformatics, 67(4):1048–1059, May 2007. URL: http://dx.doi.org/10.1002/prot.21370, doi:10.1002/prot.21370. This article has 22 citations.](https://doi.org/10.1002/prot.21370)

[12. (Düster2024Structurala) Robert Düster, Kanchan Anand, Sophie C. Binder, Maximilian Schmitz, Karl Gatterdam, Robert P. Fisher, and Matthias Geyer. Structural basis of cdk7 activation by dual t-loop phosphorylation. Nature Communications, August 2024. URL: http://dx.doi.org/10.1038/s41467-024-50891-z, doi:10.1038/s41467-024-50891-z. This article has 0 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-024-50891-z)

[13. (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. This article has 73 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M112.432005)

[14. (Shan2020Systematic) Weiwei Shan, Jiao Yuan, Zhongyi Hu, Junjie Jiang, Yueying Wang, Nicki Loo, Lingling Fan, Zhaoqing Tang, Tianli Zhang, Mu Xu, Yutian Pan, Jiaqi Lu, Meixiao Long, Janos L. Tanyi, Kathleen T. Montone, Yi Fan, Xiaowen Hu, Youyou Zhang, and Lin Zhang. Systematic characterization of recurrent genomic alterations in cyclin-dependent kinases reveals potential therapeutic strategies for cancer treatment. Cell Reports, 32(2):107884, July 2020. URL: http://dx.doi.org/10.1016/j.celrep.2020.107884, doi:10.1016/j.celrep.2020.107884. This article has 25 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.celrep.2020.107884)