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Figure 1. Reversible association of P-TEFb with the 7SK snRNP. P-TEFb is released from the 7SK snRNP by Brd4 or HIV Tat. HEXIM is ejected and the two proteins are replaced by hrRNPs. The reverse of this process requires other unknown factors.

7SK is an abundant small nuclear RNA found in metazoans. It plays a role in regulating transcription by controlling the positive transcription elongation factor P-TEFb.[1] 7SK is found in a small nuclear ribonucleoprotein complex (snRNP) with a number of other proteins that regulate the stability and function of the complex.

Composition of the 7SK snRNP

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An early study indicated that 7SK in cells is associated with a number of proteins and probing of the secondary structure suggested a model for base pairing between different regions of the RNA.[2] A breakthrough in the function of the 7SK snRNP came with the finding that the positive transcription elongation factor P-TEFb was a component of the complex.[3][4] 7SK associates with and inhibits the cyclin dependent kinase activity of P-TEFb through the action of the RNA binding proteins HEXIM1[5][6] or HEXIM2.[7][8] The gamma phosphate at the 5' end of 7SK is methylated by the methylphosphate capping enzyme MEPCE which is a constitutive component of the 7SK snRNP.[9] A La related protein LARP7 is also found associated with 7SK, presumably in part through its interaction with the 3' end of the RNA.[10][11][12] Reduction of either MEPCE or LARP7 by siRNA mediated knockdown leads to destabilization of 7SK in vivo. A subset of 7SK snRNPs lack P-TEFb and HEXIM, but contains hnRNPs instead.

Function of the 7SK snRNP

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The major function of the 7SK snRNP is control of the P-TEFb, a factor that regulates the elongation phase of transcription.[1] The kinase activity of P-TEFb is inhibited when the factor is in the 7SK snRNP. P-TEFb can be released from the 7SK snRNP by either the HIV transactivator Tat or the bromodomain containing protein BRD4. This release leads to a conformational change in 7SK RNA and the ejection of HEXIM.[13] hnRNPs stabilize the complex lacking P-TEFb and HEXIM. After P-TEFb functions on specific genes it is re-sequestered in the 7SK snRNP by an unknown mechanism. The 7SK snRNP has been characterized in both human and Drosophila.[14]

References

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  1. ^ a b Peterlin, B. Matija; Brogie, John E.; Price, David H. (2012). "7SK snRNA: a noncoding RNA that plays a major role in regulating eukaryotic transcription". Wiley Interdiscip Rev RNA. 1 (1): 92–103. doi:10.1002/wrna.106. PMC 3223291. PMID 21853533.{{cite journal}}: CS1 maint: date and year (link)
  2. ^ Wassarman, D. A.; Steitz, J. A. (1991). "Structural analyses of the 7SK ribonucleoprotein (RNP), the most abundant human small RNP of unknown function". Mol. Cell. Biol. 11 (7): 3432–45. doi:10.1128/mcb.11.7.3432-3445.1991. PMC 361072. PMID 1646389.{{cite journal}}: CS1 maint: date and year (link)
  3. ^ Nguyen, V. T.; Kiss, T.; Michels, A. A.; Bensaude, O. (2001). "7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes". Nature. 414 (6861): 322–5. doi:10.1038/35104581. PMID 11713533.{{cite journal}}: CS1 maint: date and year (link)
  4. ^ Yang, Z.; Zhu, Q.; Luo, K.; Zhou, Q. (2001). "The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription". Nature. 414 (6861): 317–22. doi:10.1038/35104575. PMID 11713532.{{cite journal}}: CS1 maint: date and year (link)
  5. ^ Michels, AA (2003). "MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner". Mol. Cell. Biol. 23 (14): 4859–69. doi:10.1128/MCB.23.14.4859-4869.2003. PMC 162212. PMID 12832472. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Yik, J. H.; Chen, R.; Nishimura, R.; Jennings, J. L.; Link, A. J.; Zhou, Q. (2003). "Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA". Mol. Cell. 12 (4): 971–82. doi:10.1016/s1097-2765(03)00388-5. PMID 14580347.{{cite journal}}: CS1 maint: date and year (link)
  7. ^ Byers, S. A.; Price, J. P.; Cooper, J. J.; Li, Q.; Price, D. H. (2005). "HEXIM2, a HEXIM1-related protein, regulates positive transcription elongation factor b through association with 7SK". J. Biol. Chem. 280 (16): 16360–7. doi:10.1074/jbc.M500424200. PMID 15713662.{{cite journal}}: CS1 maint: date and year (link)
  8. ^ Yik, J. H.; Chen, R.; Pezda, A. C.; Zhou, Q. (2005). "Compensatory contributions of HEXIM1 and HEXIM2 in maintaining the balance of active and inactive positive transcription elongation factor b complexes for control of transcription". J. Biol. Chem. 280 (16): 16368–76. doi:10.1074/jbc.M500912200. PMID 15713661.{{cite journal}}: CS1 maint: date and year (link)
  9. ^ Jeronimo, C.; Forget, D.; Bouchard, A.; Li, Q.; Chua, G.; Poitras, C.; Thérien, C.; Bergeron, D.; Bourassa, S.; Greenblatt, J.; Chabot, B.; Poirier, G. G.; Hughes, T. R.; Blanchette, M.; Price, D. H.; Coulombe, B. (2007). "Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme". Mol. Cell. 27 (2): 262–74. doi:10.1016/j.molcel.2007.06.027. PMC 4498903. PMID 17643375.{{cite journal}}: CS1 maint: date and year (link)
  10. ^ Krueger, B. J.; Jeronimo, C.; Roy, B. B.; Bouchard, A.; Barrandon, C.; Byers, S. A.; Searcey, C. E.; Cooper, J. J.; Bensaude, O.; Cohen, E. A.; Coulombe, B.; Price, D. H. (2008). "LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated". Nuc. Acids Res. 36 (7): 2219–29. doi:10.1093/nar/gkn061. PMC 2367717. PMID 18281698.{{cite journal}}: CS1 maint: date and year (link)
  11. ^ Markert, A.; Grimm, M.; Martinez, J.; Wiesner, J.; Meyerhans, A.; Meyuhas, O.; Sickmann, A.; Fischer, U. (2008). "The La-related protein LARP7 is a component of the 7SK ribonucleoprotein and affects transcription of cellular and viral polymerase II genes". EMBO Rep. 9 (6): 569–75. doi:10.1038/embor.2008.72. PMC 2427381. PMID 18483487.
  12. ^ He, N.; Jahchan, N. S.; Hong, E.; Li, Q.; Bayfield, M. A.; Maraia, R. J.; Luo, K.; Zhou, Q. (2008). "A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis". Mol. Cell. 29 (5): 588–599. doi:10.1016/j.molcel.2008.01.003. PMC 6239424. PMID 18249148.{{cite journal}}: CS1 maint: date and year (link)
  13. ^ Krueger, Brian J.; Varzavand, Katayoun; Cooper, Jeffrey J.; Price, David H. (2010). "The mechanism of release of P-TEFb and HEXIM1 from the 7SK snRNP by viral and cellular activators includes a conformational change in 7SK". PLOS ONE. 5 (8): e12335. doi:10.1371/journal.pone.0012335. PMC 2925947. PMID 20808803.{{cite journal}}: CS1 maint: date and year (link)
  14. ^ Nguyen, D.; Krueger, B. J.; Sedore, S. C.; Brogie, J. E.; Rogers, J. T.; Rajendra, T. K.; Saunders, A.; Matera, A. G.; Lis, J. T.; Uguen, P.; Price, D. H. (2012). "The Drosophila 7SK snRNP and the essential role of dHEXIM in development". Nuc. Acids Res. 40 (12): 5283–5297. doi:10.1093/nar/gks191. PMC 3384314. PMID 22379134.
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