CDK12 and Integrator-PP2A complex modulates LEO1 phosphorylation for processive transcription elongation
Min Qiu1, Zhinang Yin1, Honghong Wang1
1Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Science Advances
|May 19, 2023
Summary
Cyclin-dependent kinase 12 (CDK12) regulates gene transcription by phosphorylating LEO1, a key protein in the PAF1C complex. This phosphorylation impacts RNA polymerase II activity and transcription elongation, revealing new regulatory mechanisms.
Area of Science:
- Molecular Biology
- Gene Regulation
- Biochemistry
Background:
- Cyclin-dependent kinase 12 (CDK12) forms a nuclear kinase with cyclin K.
- CDK12 phosphorylates RNA polymerase II (Pol II) to promote transcription elongation.
- Understanding CDK12 substrates is crucial for elucidating its cellular functions.
Purpose of the Study:
- To identify nuclear substrates of CDK12.
- To investigate the role of CDK12 in regulating transcription, chromatin organization, and RNA splicing.
- To characterize the function of LEO1 within the CDK12 pathway.
Main Methods:
- Chemical genetic screening
- Phosphoproteomic screening
- Depletion studies
- Site-directed mutagenesis
- Co-immunoprecipitation assays
Main Results:
- Identified a landscape of nuclear CDK12 substrates involved in transcription and RNA processing.
- Validated LEO1, a subunit of the polymerase-associated factor 1 complex (PAF1C), as a CDK12 substrate.
- Demonstrated that LEO1 phosphorylation by CDK12 is essential for PAF1C association with elongating Pol II and processive transcription.
- Discovered that the Integrator-PP2A complex (INTAC) dephosphorylates LEO1, and INTAC depletion enhances PAF1C-Pol II association.
Conclusions:
- CDK12 regulates LEO1 phosphorylation, impacting PAF1C function and transcription elongation.
- INTAC plays a counter-regulatory role by dephosphorylating LEO1.
- This study uncovers a novel regulatory axis involving CDK12, LEO1, and INTAC in gene transcription control.
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