CDK7-CDK11 axis in spliceosome regulation and pre-mRNA splicing.

Area of Science:

• Molecular Biology
• Gene Regulation
• Cellular Processes

Background:

• Cyclin-dependent kinase 11 (CDK11) is vital for pre-mRNA splicing through SF3B1 phosphorylation.
• Understanding CDK11 regulation is key, as SF3B1 phosphorylation marks active spliceosomes.

Purpose of the Study:

• To investigate the regulatory mechanisms of CDK11.
• To elucidate the role of CDK11 Thr595 phosphorylation in spliceosome activation and function.

Main Methods:

• Mutational analysis to assess the function of CDK11 Thr595.
• Investigating CDK11 association with CDK7 and its impact on transcription and splicing.
• SILAC-based phosphoproteomics to identify CDK11 substrates.

Main Results:

• CDK11 Thr595 phosphorylation is essential for active CDK11 complex formation with cyclin L and SAP30BP.
• CDK7 inhibition leads to splicing defects, correlating with dephosphorylation of CDK11 Thr595 and SF3B1.
• SF3B1, CDC5L, and ESS2 identified as novel CDK11 substrates.

Conclusions:

• CDK7 likely regulates pre-mRNA splicing by phosphorylating CDK11 at Thr595.
• CDK11 plays a broader role in spliceosome regulation beyond SF3B1 phosphorylation.