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7SK snRNA: a noncoding RNA that plays a major role in regulating eukaryotic transcription

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The human 7SK small nuclear RNA (snRNA) is an abundant noncoding RNA whose function has been conserved in evolution from invertebrates to humans. It is transcribed by RNA polymerase III (RNAPIII) and is located in the nucleus. Together with associated cellular proteins, 7SK snRNA regulates the activity of the positive transcription elongation factor b (P‐TEFb). In humans, this regulation is accomplished by the recruitment of P‐TEFb by the 7SK snRNA‐binding proteins, hexamethylene bisacetamide (HMBA)‐induced mRNA 1/2 (HEXIM1 or HEXIM2), which inhibit the kinase activity of P‐TEFb. P‐TEFb regulates the transition of promoter proximally paused RNA polymerase II (RNAPII) into productive elongation, thereby, allowing efficient mRNA production. The protein composition of the 7SK small nuclear ribonucleoprotein (snRNP) is regulated dynamically. While the Lupus antigen (La)‐related protein 7 (LARP7) is a constitutive component, the methylphosphate capping enzyme (MePCE) associates secondarily to phosphorylate the 5′ end of 7SK snRNA. The release of active P‐TEFb is closely followed by release of HEXIM proteins and both are replaced by heterogeneous nuclear ribonucleoproteins (hnRNPs). The released P‐TEFb activates the expression of most cellular and viral genes. Regulated release of P‐TEFb determines the expression pattern of many of the genes that respond to environmental stimuli and regulate growth, proliferation, and differentiation of cells. WIREs RNA 2012, 3:92–103. doi: 10.1002/wrna.106

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Figure 1.

Conserved 7SK small nuclear RNA (snRNA) motifs. (a) Structure of 7SK snRNA proposed by Wassarman and Steitz.21 Residues in paired regions that were sensitive to N‐cyclohexyl‐N‐(β‐[N‐methylmorpholino]ethyl)carbodiimide p‐toluenesulfonate (CMCT) are indicated. (b) Detailed structure of the human 7SK snRNA showing possible structural pairing based on conservation of sequences across many species.22 Structural motifs (M) are numbered from M1 to M8 and correspond with the regions of highest conservation. Colored boxes indicate motifs that have been determined to be important for binding of proteins to 7SK snRNA. M1 involves base pairing between the two termini of the RNA bringing them into a relatively close proximity and potentially aiding in protein interactions. M3 is a stem–loop required for the binding of HEXIM. M8 is a stem–loop near the 3′ end that is necessary for positive transcription elongation factor b (P‐TEFb) association. (c) Simplified cartoon model of 7SK RNA showing the important structural motifs corresponding to the colors of the detailed structure in (b). The images in (a) and (b) are based on a figure in Marz et al.22

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Figure 2.

Reversible association of positive transcription elongation factor b (P‐TEFb) and HEXIM with the 7SK small nuclear ribonucleoprotein (snRNP). Cyclic model for interactions between P‐TEFb and the 7SK snRNP. Left: the 7SK snRNP containing the indicated proteins is acted upon directly by Tat and bromo domain‐containing protein 4 (Brd4),32 or by ultraviolet (UV) light, actinomycin D, any P‐TEFb inhibitor, HMBA, or suberoylanilide hydroxamic acid (SAHA) (release). P‐TEFb is extracted from the snRNP, which causes the subsequent release of HEXIM. Right: after release of P‐TEFb and HEXIM, there is a conformational change in the RNA that is stabilized by heterogeneous nuclear ribonucleoproteins (hnRNPs). Lupus antigen (La)‐related protein 7 (LARP7) and methylphosphate capping enzyme (MePCE) remain associated with 7SK small nuclear RNA (snRNA). The release of P‐TEFb and HEXIM is not directly reversible and the mechanism involved in re‐sequestration of HEXIM and then P‐TEFb remains unknown.

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Figure 3.

Control of HIV transcription by Tat. (1) The binding between Tat and positive transcription elongation factor b (P‐TEFb) releases P‐TEFb from the 7SK snRNP, and (2) a Tat–P‐TEFb complex is delivered to the promoter proximally paused RNA polymerase II (RNAPII) on the HIV long terminal repeat (LTR) through an interaction with transactivation response (TAR), which is present in all nascent viral transcripts. Upon delivery of P‐TEFb, the negative elongation factor (NELF) is phosphorylated and removed. 5,6‐Dichloro‐1‐β‐D‐ribofuranosylbenzimidazole (DRB)‐sensitivity inducing factor (DSIF) is also phosphorylated (P) and facilitates the transition of RNAPII into productive elongation.

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