Cyclin T1

Cyclin T1 is a protein that functions as a regulatory subunit of the positive transcription elongation factor b (P-TEFb) complex. P-TEFb is a kinase that phosphorylates the C-terminal domain (CTD) of RNA polymerase II, releasing it from promoter-proximal pausing and allowing transcriptional elongation to proceed. Cyclin T1 is specifically associated with CDK9 (cyclin-dependent kinase 9), forming the active kinase complex.

Function:

Cyclin T1's primary role is to bind to and activate CDK9. This binding is crucial for the proper folding and stabilization of CDK9, preventing its degradation. The Cyclin T1-CDK9 complex then phosphorylates the CTD of RNA polymerase II, as well as other substrates involved in transcription elongation, such as SPT5 and negative elongation factor (NELF). This phosphorylation overcomes the pausing imposed by NELF and DSIF (DRB sensitivity-inducing factor) factors, allowing efficient elongation of mRNA transcripts. P-TEFb is essential for the expression of a wide range of genes, including those involved in cell growth, differentiation, and apoptosis.

Regulation:

The activity and availability of Cyclin T1 are tightly regulated. Its expression levels can be influenced by various cellular signals and developmental cues. Furthermore, Cyclin T1 can be sequestered in inactive complexes, preventing its association with CDK9. The displacement of Cyclin T1 from these complexes is often required for P-TEFb activation.

Clinical Significance:

Cyclin T1 has been implicated in various diseases, most notably in its interaction with the HIV-1 Tat protein. Tat recruits P-TEFb to the viral long terminal repeat (LTR) promoter, dramatically enhancing viral transcription. This interaction is crucial for HIV-1 replication. Mutations in Cyclin T1 have also been linked to certain cancers and developmental disorders. For example, alterations in the CCNT1 gene (which encodes Cyclin T1) have been associated with facio-auriculo-vertebral (FAV) spectrum, also known as Oculo-Auriculo-Vertebral Spectrum (OAVS) or hemifacial microsomia. Dysregulation of Cyclin T1 and P-TEFb can contribute to uncontrolled cell growth and tumor formation.