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 involved in nuclear RNA surveillance pathways, ensuring RNA fidelity by detecting and degrading defective transcripts, and is also associated with syndromic intellectual disability [1,2].

Mutations in Cdk13 can lead to oncogenic effects. In melanoma, patient-mutated Cdk13 accelerates zebrafish melanoma by impeding nuclear RNA surveillance, causing aberrant RNA stabilization [1]. In triple-negative breast cancer, inhibiting Cdk12/13 triggers intronic polyadenylation site cleavage, suppressing DNA damage response proteins and creating a “BRCAness” phenotype [3]. In prostate cancer, Cdk13 promotes lipid deposition and cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA [4]. In colorectal cancer, Cdk13 phosphorylates translation machinery components 4E-BP1 and eIF4B, promoting tumorigenic protein synthesis [6].

In conclusion, Cdk13 is crucial for gene transcription-related processes and its dysregulation is associated with multiple cancers including melanoma, triple-negative breast cancer, prostate cancer, and colorectal cancer. Functional studies in zebrafish and in cell-based models have revealed its role in promoting tumorigenesis through various mechanisms such as affecting RNA surveillance, DNA damage response, lipid metabolism, and protein synthesis [1,3,4,6].

References:

1. 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/

2. 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/

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/