CDK9: A Key regulator of RNA Polymerase II Transcription

Shayan Ahmed, Jamia Millia Islamia, New Delhi

It has been discovered that Cyclin-Dependent Kinase 9 (CDK9) is an important regulator of RNA Polymerase II transcription. As a regulator CDK9 works across the transcription unit at multiple locations. These include the transcriptional pause release before elongation by the action of positive transcription elongation factor b (P-TEFb). Therefore, it is crucial to understand the transcriptional regulatory networks that surround CDK9. This will assist researchers to figure out how transcriptional regulatory networks are controlled throughout development, stress, and signalling-induced activation.

CDK9 & Transcription factor P‑TEFb

Cyclin-Dependent Kinases (CDKs) are a family of various serine/threonine kinases. These are known to play a role of significance in both cell division and transcription via RNA Polymerase II (RNAPII). Among all the CDKs, the most extensively studied transcriptional CDK is CDK9. 

CDK9 is a nuclear protein that is found throughout the human body, with greater amounts in terminally differentiated cells. CDK9(42) and CDK9(55) are two isoforms of CDK9 that are produced from the same gene and have different molecular weights. CDK9 produces the transcription factor P-TEFb by associating with a cyclin T subunit. Most RNAPII-transcribed genes require P-TEFb for efficient transcription. P-TEFb promotes productive elongation by releasing stalled RNAPII from the promoter into gene bodies. To maintain the correct transcriptional output, precise control of CDK9 activity is essential. CDK9 forms heterodimeric complexes with Cyclin T1, T2a, or T2b; CDK9/CycT heterodimer is considered as the elongation factor, P-TEFb. CDK9 must not only be associated with a Cyclin T, it should also be phosphorylated on the threonine 186 residue.

Role of P‑TEFb in RNAPII transcription
When RNAPII initiates RNA molecule synthesis and crosses the promoter, the transition to elongation takes place. Movement into the gene is typically inhibited following initiation and promoter escape. This occurs at an early elongation checkpoint (EEC) 30–60 bp downstream from the transcription start site (TSS). Abortive transcription occurs when the RNAPII transcription complex fails to convert to productive elongation at this step. P-TEFb activity is required for the release of RNAPII from the EEC. The frequency of transcription initiation has recently been demonstrated to be influenced by CDK9-mediated RNAPII pause release. The coordinated activity of the negative elongation factor (NELF) and DRB-sensitivity inducing factor (DSIF) stops the advancement of RNAPII. Also, the protein phosphatase 4 (PP4) enzyme assists in keeping the DSIF Spt5 subunit unphosphorylated. After being recruited, the P-TEFb phosphorylates DSIF, NELF, and the C terminal domain of RNAPII. When Spt5 is phosphorylated, DSIF becomes a positive elongation factor, and NELF is expelled from the RNAPII complex. Inhibitory phosphorylation of PP4 further strengthened the phosphorylation of Spt5. Following pause release, the elongation complex is joined by certain accessory proteins the further enhance the activity of RNAPII. As a result, the rate of elongation is increased.

Figure 1. A schematic representation of the Transcription model depicting the role of association of CDK9 with Cyclin T, forming P-TEFb, participating in the regulation of transcription. CDK9 is also associated with the regulation of termination.

Other Roles of CDK9 in Transcription

CDK9 is also involved in the regulation of transcription across the polyA site. PP4 and PP1 phosphatase activities are inactivated by CDK9 phosphorylation during elongation, resulting in high levels of Spt5 phosphorylation. The Ser2P recruits the cleavage and polyadenylation machinery (CPA) after RNAPII transcribes via the polyA (pA) site, which is necessary for appropriate termination. Simultaneously, CDK9 activity decreases, and PP1 activity increases, resulting in Spt5 dephosphorylation. The unphosphorylated Spt5 functions as a brake for RNAPII, which therefore becomes a preferred substrate for CDK9-activated Xrn2 exonuclease. Thus, CDK9 is crucial in controlling the elongation to termination transition.

CDK9 & Associated DiseasesCDK9 plays a key role in regulating gene expression and maintaining cellular homeostasis. Also, CDK9 activity is associated with a variety of pathologic diseases. The Human Immunodeficiency Virus (HIV) requires P-TEFb as a cellular cofactor for transcription and replication. Inappropriate activity of CDK9 also results in cancer development and cardiac hypertrophy. Therefore, CDK9 serves as an attractive target for the development of novel cancer therapies. There are high expectations that inhibiting CDK9 activity may effectively and selectively limit cell proliferation.

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Source:

Egloff S. (2021). CDK9 keeps RNA polymerase II on track. Cellular and molecular life sciences : CMLS, 10.1007/s00018-021-03878-8. Advance online publication. https://doi.org/10.1007/s00018-021-03878-8

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About Author: Shayan Ahmed is currently pursuing a Master of Science degree in Microbiology from the Department of Biosciences, Jamia Millia Islamia, New Delhi. His area of research interest lies in antibiotic resistance and associated molecular mechanisms. His recent work was focused on understanding colistin resistance patterns in the environment, particularly in water bodies.