Figure 4.

The regulation of P-TEFb in growing cells. In growing, dividing cells, P-TEFb partitions between the active (free) state and the inactive (sequestered) form. In the former, it binds other transcription factors (TFs) or is incorporated into the super elongation complex (SEC). In the latter, it is incorporated into the 7SK small nuclear ribonucleoprotein (7SK snRNP) complex by 7SK snRNA and HEXIM1. 7SK snRNA is stabilized by the La related protein 7 (LARP7) and methyl phosphate capping enzyme (MePCE) at its 3’ and 5’ ends, respectively. P-TEFb is released by stress from the 7SK snRNP, which increases the synthesis of HEXIM1. Thus, 7SK snRNP reassembles quickly. Stress can come in many forms, from cellular signaling pathways, certain signaling molecules (cytokines and lymphokines), DNA damage (e.g. UV light) to chromatin stress (HDAC and BET bromodomain protein inhibition), differentiation agents (HMBA) and viral infections. Of interest, HEXIM1 and P-TEFb bind to the 5’ bulge and central loop in stem loop 1 of 7SK snRNA, which is analogous to how Tat interacts with TAR RNA. Indeed, Tat can displace P-TEFb from the 7SK snRNP.