Cdk13-KO Mouse

CDK13, a cyclin-dependent kinase, phosphorylates the C-terminal domain of RNA polymerase II, regulating transcription and co-transcriptional processes [3,5,7]. It is also implicated in nuclear RNA surveillance, lipid metabolism, and protein synthesis pathways [2,4,6]. Mutations in CDK13 have been linked to syndromic intellectual disability, with characteristic craniofacial features, feeding difficulties in infancy, and structural heart or brain malformations [1].

Mutations in CDK13 accelerate zebrafish melanoma by impeding nuclear RNA surveillance, causing aberrant RNA stabilization [2]. In triple-negative breast cancer, inhibition of CDK13 (along with CDK12) triggers intronic polyadenylation site cleavage, suppressing DNA damage response proteins and promoting sensitivity to chemotherapy and PARP inhibitors [3]. In prostate cancer, CDK13 promotes lipid deposition and cancer progression via the NSUN5-mediated m5C modification of ACC1 mRNA [4]. Also, CDK13 phosphorylates translation machinery components 4E-BP1 and eIF4B, promoting tumorigenic protein synthesis in colorectal cancer [6].

In summary, CDK13 is crucial in transcription-related processes and is involved in multiple disease conditions such as intellectual disability and various cancers. Functional studies in model organisms like zebrafish and in cancer cell lines have revealed its diverse roles in disease-related biological processes, providing potential therapeutic targets for these diseases.

References:

1. Hamilton, Mark James, Suri, Mohnish. 2018. CDK13-related disorder. In Advances in genetics, 103, 163-182. doi:10.1016/bs.adgen.2018.11.001. https://pubmed.ncbi.nlm.nih.gov/30904094/

2. Insco, Megan L, Abraham, Brian J, Dubbury, Sara J, Boutz, Paul L, Zon, Leonard I. 2023. Oncogenic CDK13 mutations impede nuclear RNA surveillance. In Science (New York, N.Y.), 380, eabn7625. doi:10.1126/science.abn7625. https://pubmed.ncbi.nlm.nih.gov/37079685/

3. Quereda, Victor, Bayle, Simon, Vena, Francesca, Roush, William R, Duckett, Derek R. 2019. Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer. In Cancer cell, 36, 545-558.e7. doi:10.1016/j.ccell.2019.09.004. https://pubmed.ncbi.nlm.nih.gov/31668947/

4. Zhang, Yong, Chen, Xiao-Nan, Zhang, Hong, Qu, Chang-Bao, Yang, Zhan. 2023. CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA. In Cell death and differentiation, 30, 2462-2476. doi:10.1038/s41418-023-01223-z. https://pubmed.ncbi.nlm.nih.gov/37845385/

5. Zhang, Tinghu, Kwiatkowski, Nicholas, Olson, Calla M, Young, Richard A, Gray, Nathanael S. 2016. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. In Nature chemical biology, 12, 876-84. doi:10.1038/nchembio.2166. https://pubmed.ncbi.nlm.nih.gov/27571479/

6. Wu, Chao, Xie, Ting, Guo, Ying, Liang, Kaiwei, Liu, Hudan. 2023. CDK13 phosphorylates the translation machinery and promotes tumorigenic protein synthesis. In Oncogene, 42, 1321-1330. doi:10.1038/s41388-023-02653-2. https://pubmed.ncbi.nlm.nih.gov/36882522/

7. Greenleaf, Arno L. 2018. Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium. In Transcription, 10, 91-110. doi:10.1080/21541264.2018.1535211. https://pubmed.ncbi.nlm.nih.gov/30319007/