Figure 1

Composition and assembly of P-TEFb complexes. A) 7SK snRNA contains 5'- and 3'- ends with pppG (triphosphate guanosine) and UUUU-OH (oligouridylate tail), respectively. 7SKsnRNA is recognized by MEPCE (7SK snRNA methylphosphate capping enzyme) and LARP7 (La-related protein 7). B) MEPCE methylates gamma-phosphate of its first 5'ribonucleotide, depicted by an asterisk, and LARP7 stabilizes 7SK snRNA by binding to its oligouridylate tail. Hexim1 (Hex1) homodimerizes (or heterodimerizes with Hexim2) via its coiled-coil domain in the C-terminus, but N-terminus adopts conformation which does not allow binding to P-TEFb (CDK9/Cyc). C) Binding of 7SK snRNA from 7SK snRNA/MEPCE/LARP7 complex to basic region in central part of Hexim1 triggers conformational changes of hexim dimer leading to exposition of CycT1-binding domain at the C-terminus of Hex1 and consequent binding of P-TEFb ('SMALL' complex). D) The 'LARGE' complex is formed and is stabilized due to multiple protein-protein and protein-RNA contacts within the complex. Activity of P-TEFb is inhibited in the large complex. Several stimuli have been reported to disrupt the large complex, such as UV radiation, diverse stress signals (mechanical, hypertrophic), cytokines (TNF-α, IL-6) and inhibitors (Actinomycin D, DRB).