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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
Published on: May 3, 2018
Gene expression regulation by CDK12: a versatile kinase in cancer with functions beyond CTD phosphorylation
Seung Hyuk Choi1, Seongjae Kim2, Katherine A Jones3
1Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, 92037, USA. sechoi@salk.edu.
Abstract:
Cyclin-dependent kinases (CDKs) play critical roles in cell cycle progression and gene expression regulation. In human cancer, transcription-associated CDKs can activate oncogenic gene expression programs, whereas cell cycle-regulatory CDKs mainly induce uncontrolled proliferation. Cyclin-dependent kinase 12 (CDK12) belongs to the CDK family of serine/threonine kinases and has been recently found to have multiple roles in gene expression regulation and tumorigenesis. Originally, CDK12 was thought to be one of the transcription-associated CDKs, acting with its cyclin partner Cyclin K to promote the phosphorylation of the C-terminal domain (CTD) of RNA polymerase II and induce transcription elongation. However, recent studies have demonstrated that CDK12 also controls multiple gene expression processes, including transcription termination, mRNA splicing, and translation. Most importantly, CDK12 mutations are frequently found in human tumors. Loss of CDK12 function causes defective expression of DNA damage response (DDR) genes, which eventually results in genome instability, a hallmark of human cancer. Here, we discuss the diverse roles of CDK12 in gene expression regulation and human cancer, focusing on newly identified CDK12 kinase functions in cellular processes and highlighting CDK12 as a promising therapeutic target for human cancer treatment.
Insights
Cyclin-dependent kinase 12 (CDK12) regulates gene expression and is crucial in preventing genome instability in human cancers. Loss of CDK12 function is linked to cancer development, making it a potential therapeutic target.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- Cyclin-dependent kinases (CDKs) are key regulators of cell cycle and gene expression.
- CDK12, a serine/threonine kinase, has diverse roles in gene expression and tumorigenesis.
- CDK12 mutations are prevalent in human tumors, leading to genomic instability.
Purpose of the Study:
- To discuss the multifaceted roles of CDK12 in gene expression regulation.
- To highlight CDK12's functions in cellular processes beyond transcription elongation.
- To emphasize CDK12 as a potential therapeutic target for human cancer.
Main Methods:
- Review of recent studies on CDK12 function and its role in cancer.
- Analysis of CDK12's involvement in transcription, splicing, and translation.
- Examination of the consequences of CDK12 loss-of-function mutations.
Main Results:
- CDK12 regulates transcription elongation, termination, mRNA splicing, and translation.
- Loss of CDK12 function impairs DNA damage response (DDR) gene expression.
- Defective DDR gene expression due to CDK12 loss results in genome instability.
Conclusions:
- CDK12 plays critical roles in maintaining genome stability through regulation of gene expression.
- Altered CDK12 function contributes to human tumorigenesis.
- CDK12 represents a promising therapeutic target for cancer treatment.
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