Hexim1, an RNA-controlled protein hub

Abstract

Hexim1 acts as a tumor suppressor and is involved in the regulation of innate immunity. It was initially described as a non-coding RNA-dependent regulator of transcription. Here, we detail how 7SK RNA binds to Hexim1 and turns it into an inhibitor of the positive transcription elongation factor (P-TEFb). In addition to its action on P-TEFb, it plays a role in a variety of different mechanisms: it controls the stability of transcription factor components and assists binding of transcription factors to their targets.

Keywords: 7SK; CDK9; NEAT1; P-TEFb; eukaryotic transcription; innate immunity; melanoma; nucleotide depletion; transcription regulation; transcriptional elongation.

Figure 1.

– (A) Hexim domain architecture. Amino-acid numbers delimiting the basic region (BR), the central region (CR), the PYNT motif, the acidic regions (AR1 and AR2) and the C-terminal helices (α1, α2 and α3) are indicated. (B) 3-D structure of Hexim1 C-terminal coiled-coil domain deduced from NMR (pdb – 2gd7). Hexim1 forms dimers through its C-terminal domain. Helices α2 and α3 are separated by a GGD a.a. sequence. (C) The basic region (BR), the PYNT motif and acidic regions (AR1 and AR2) are schematically positioned. The BR and AR1 regions interact within “free” Hexim1 dimers. (D) Binding of Hexim1 to 7SK RNA releases the BR/AR interaction leading to Hexim1 sequences between a.a. 260 and 310 binding to Cyclin T1 (CycT1) and the PYNT sequence binding to Cdk9 catalytic cleft. resulting in inhibition of Cdk9/Cyclin T1 (P-TEFb) kinase activity. MePCE and LaRP7 proteins bind to 7SK 5’ and 3’ extremities, respectively. The same color codes are used for Hexim 1 regions in A, B, C and D.