The Role of Cyclin T1 in the Human P-TEFb Complex: Key Regulator of Transcription Elongation

14. The positive transcription elongation factor. P-TEFb, is a Mufti-protein complex that plays an essential role in the regulation of transcription by RNA polymerase II (POI II) in eukaryotes. Human P-TEFb is a cyclin dependent kinase (cdk9) and has the unique regulatory cyclins
(1) cyclin D          (2) Cyclin K
(3) cyclin E            (4) Cyclin T1

The positive transcription elongation factor b (P-TEFb) is a critical multi-protein complex that regulates transcription elongation by RNA polymerase II (Pol II) in eukaryotic cells. It plays a pivotal role in transitioning Pol II from a paused state near gene promoters into productive elongation, enabling efficient synthesis of messenger RNA (mRNA).

Composition of Human P-TEFb

Human P-TEFb is a cyclin-dependent kinase complex primarily composed of:

• Cdk9 (Cyclin-dependent kinase 9): The catalytic subunit responsible for phosphorylating target proteins.

• Cyclin T1: The unique regulatory cyclin subunit that binds Cdk9, activating its kinase activity and targeting it to specific transcriptional sites.

In addition to cyclin T1, human P-TEFb can also associate with other cyclins such as cyclin T2 and cyclin K, but cyclin T1 is the most well-characterized and predominant regulatory partner in the context of transcription elongation.

Function of P-TEFb in Transcription

Immediately after transcription initiation, RNA polymerase II often pauses near the promoter region. P-TEFb facilitates the release of this paused polymerase by phosphorylating:

• The carboxyl-terminal domain (CTD) of Pol II, specifically on serine 2 residues.

• Negative elongation factors such as NELF and DSIF, which contribute to pausing.

Phosphorylation by P-TEFb converts Pol II into an elongation-competent form, allowing it to synthesize full-length transcripts.

Importance of Cyclin T1

Cyclin T1 is essential for:

• Activating Cdk9 kinase activity.

• Recruiting P-TEFb to gene promoters, often through interactions with transcription factors or viral proteins such as HIV Tat.

• Mediating the structural conformation of P-TEFb, as revealed by X-ray crystallography studies showing extensive contacts between cyclin T1 and Cdk9.

The interaction between HIV Tat and cyclin T1 is critical in HIV transcription regulation, highlighting cyclin T1’s broader biological significance.

Other Cyclins in P-TEFb

While cyclin T1 is the primary regulatory subunit, P-TEFb can also incorporate:

• Cyclin T2 (T2a and T2b isoforms)

• Cyclin K

However, cyclin D and cyclin E are not regulatory subunits of P-TEFb.

Correct Answer to the Query

The unique regulatory cyclin associated with human P-TEFb is:

(4) Cyclin T1

Summary

Human P-TEFb is a complex of Cdk9 and cyclin T1 that plays a crucial role in regulating transcription elongation by RNA polymerase II. Cyclin T1 activates Cdk9 and directs P-TEFb to paused polymerases, facilitating the transition to productive elongation. Understanding this complex is vital for insights into gene regulation and therapeutic targets, especially in diseases like HIV.