7SK RNA

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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. Regulation of P-TEFb by the 7SK snRNP.jpg
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 RNA
RF00100.jpg
Predicted secondary structure and sequence conservation of 7SK
Identifiers
Symbol7SK
Rfam RF00100
Other data
RNA type Gene
Domain(s) Eukaryota
SO SO:0000274
PDB structures PDBe
RN7SK
Identifiers
SymbolRN7SK
NCBI gene 125050
Other data
Locus Chr. 6 p12.2

In molecular biology 7SK is an abundant small nuclear RNA found in metazoans. [1] It plays a role in regulating transcription by controlling the positive transcription elongation factor P-TEFb. [2] 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.

Contents

Structure

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. [3] 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. [4] [5] 7SK associates with and inhibits the cyclin dependent kinase activity of P-TEFb through the action of the RNA binding proteins HEXIM1 [6] [7] or HEXIM2. [8] [9] 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. [10] A La related protein LARP7 is also found associated with 7SK, presumably in part through its interaction with the 3' end of the RNA. [11] [12] [13] 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. [14]

Function

The major function of the 7SK snRNP is control of the P-TEFb, a factor that regulates the elongation phase of transcription. [2] 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. [15] 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. [16] Detailed review. [14]

Related Research Articles

Cell cycle Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm and other components into two daughter cells in a process called cell division.

SR protein

SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respectively. SR proteins are ~200-600 amino acids in length and composed of two domains, the RNA recognition motif (RRM) region and the RS domain. SR proteins are more commonly found in the nucleus than the cytoplasm, but several SR proteins are known to shuttle between the nucleus and the cytoplasm.

Cyclin D

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

Cyclin-dependent kinase 2

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

P-TEFb

The positive transcription elongation factor, P-TEFb, is a multiprotein complex that plays an essential role in the regulation of transcription by RNA polymerase II in eukaryotes. Immediately following initiation Pol II becomes trapped in promoter proximal paused positions on the majority of human genes. P-TEFb is a cyclin dependent kinase that can phosphorylate the DRB sensitivity inducing factor (DSIF) and negative elongation factor (NELF), as well as the carboxyl terminal domain of the large subunit of Pol II and this causes the transition into productive elongation leading to the synthesis of mRNAs. P-TEFb is regulated in part by a reversible association with the 7SK snRNP. Treatment of cells with the P-TEFb inhibitors DRB or flavopidirol leads to loss of mRNA production and ultimately cell death.

U1 spliceosomal RNA

U1 spliceosomal RNA is the small nuclear RNA (snRNA) component of U1 snRNP, an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs. Splicing, or the removal of introns, is a major aspect of post-transcriptional modification, and takes place only in the nucleus of eukaryotes.

Cyclin-dependent kinase 9

Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb.

Cyclin T1

Cyclin-T1 is a protein that in humans is encoded by the CCNT1 gene.

Cyclin-dependent kinase 7

Cyclin-dependent kinase 7, or cell division protein kinase 7, is an enzyme that in humans is encoded by the CDK7 gene.

HNRNPK

Heterogeneous nuclear ribonucleoprotein K is a protein that in humans is encoded by the HNRNPK gene. It is found in the cell nucleus that binds to pre-messenger RNA (mRNA) as a component of heterogeneous ribonucleoprotein particles. The simian homolog is known as protein H16. Both proteins bind to single-stranded DNA as well as to RNA and can stimulate the activity of RNA polymerase II, the protein responsible for most gene transcription. The relative affinities of the proteins for DNA and RNA vary with solution conditions and are inversely correlated, so that conditions promoting strong DNA binding result in weak RNA binding.

MNAT1

CDK-activating kinase assembly factor MAT1 is an enzyme that in humans is encoded by the MNAT1 gene.

snRNP70

snRNP70 also known as U1 small nuclear ribonucleoprotein 70 kDa is a protein that in humans is encoded by the SNRNP70 gene. snRNP70 is a small nuclear ribonucleoprotein that associates with U1 spliceosomal RNA, forming the U1snRNP a core component of the spliceosome. The U1-70K protein and other components of the spliceosome complex form detergent-insoluble aggregates in both sporadic and familial human cases of Alzheimer's disease. U1-70K co-localizes with Tau in neurofibrillary tangles in Alzheimer's disease.

SUPT5H

Transcription elongation factor SPT5 is a protein that in humans is encoded by the SUPT5H gene.

Cyclin H

Cyclin-H is a protein that in humans is encoded by the CCNH gene.

Cyclin-dependent kinase 8

Cell division protein kinase 8 is an enzyme that in humans is encoded by the CDK8 gene.

HEXIM1

Protein HEXIM1 is a protein that in humans is encoded by the HEXIM1 gene.

Cyclin T2

Cyclin-T2 is a protein that in humans is encoded by the CCNT2 gene.

Cyclin K

Cyclin-K is a protein that in humans is encoded by the CCNK gene.

HEXIM2

Protein HEXIM2 is a protein that in humans is encoded by the HEXIM2 gene.

RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins.

References

  1. ↑ Diribarne G, Bensaude O (2009). "7SK RNA, a non-coding RNA regulating P-TEFb, a general transcription factor". RNA Biology. 6 (2): 122–8. doi: 10.4161/rna.6.2.8115 . PMID   19246988.
  2. 1 2 Peterlin BM, Brogie JE, Price DH (2012). "7SK snRNA: a noncoding RNA that plays a major role in regulating eukaryotic transcription". Wiley Interdisciplinary Reviews. RNA. 3 (1): 92–103. doi:10.1002/wrna.106. PMC   3223291 . PMID   21853533.
  3. ↑ Wassarman DA, Steitz JA (July 1991). "Structural analyses of the 7SK ribonucleoprotein (RNP), the most abundant human small RNP of unknown function". Molecular and Cellular Biology. 11 (7): 3432–45. doi:10.1128/MCB.11.7.3432. PMC   361072 . PMID   1646389.
  4. ↑ Nguyen VT, Kiss T, Michels AA, Bensaude O (November 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. S2CID   4341651.
  5. ↑ Yang Z, Zhu Q, Luo K, Zhou Q (November 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. S2CID   4379065.
  6. ↑ Michels AA, Nguyen VT, Fraldi A, Labas V, Edwards M, Bonnet F, et al. (July 2003). "MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner". Molecular and Cellular Biology. 23 (14): 4859–69. doi:10.1128/MCB.23.14.4859-4869.2003. PMC   162212 . PMID   12832472.
  7. ↑ Yik JH, Chen R, Nishimura R, Jennings JL, Link AJ, Zhou Q (October 2003). "Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA". Molecular Cell. 12 (4): 971–82. doi:10.1016/S1097-2765(03)00388-5. PMID   14580347.
  8. ↑ Byers SA, Price JP, Cooper JJ, Li Q, Price DH (April 2005). "HEXIM2, a HEXIM1-related protein, regulates positive transcription elongation factor b through association with 7SK". The Journal of Biological Chemistry. 280 (16): 16360–7. doi: 10.1074/jbc.M500424200 . PMID   15713662.
  9. ↑ Yik JH, Chen R, Pezda AC, Zhou Q (April 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". The Journal of Biological Chemistry. 280 (16): 16368–76. doi: 10.1074/jbc.M500912200 . PMID   15713661.
  10. ↑ Jeronimo C, Forget D, Bouchard A, Li Q, Chua G, Poitras C, et al. (July 2007). "Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme". Molecular Cell. 27 (2): 262–74. doi:10.1016/j.molcel.2007.06.027. PMC   4498903 . PMID   17643375.
  11. ↑ Krueger BJ, Jeronimo C, Roy BB, Bouchard A, Barrandon C, Byers SA, et al. (April 2008). "LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated". Nucleic Acids Research. 36 (7): 2219–29. doi:10.1093/nar/gkn061. PMC   2367717 . PMID   18281698.
  12. ↑ Markert A, Grimm M, Martinez J, Wiesner J, Meyerhans A, Meyuhas O, et al. (June 2008). "The La-related protein LARP7 is a component of the 7SK ribonucleoprotein and affects transcription of cellular and viral polymerase II genes". EMBO Reports. 9 (6): 569–75. doi:10.1038/embor.2008.72. PMC   2427381 . PMID   18483487.
  13. ↑ He N, Jahchan NS, Hong E, Li Q, Bayfield MA, Maraia RJ, et al. (March 2008). "A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis". Molecular Cell. 29 (5): 588–99. doi:10.1016/j.molcel.2008.01.003. PMC   6239424 . PMID   18249148.
  14. 1 2 C Quaresma AJ, Bugai A, Barboric M (September 2016). "Cracking the control of RNA polymerase II elongation by 7SK snRNP and P-TEFb". Nucleic Acids Research. 44 (16): 7527–39. doi:10.1093/nar/gkw585. PMC   5027500 . PMID   27369380.
  15. ↑ Krueger BJ, Varzavand K, Cooper JJ, Price DH (August 2010). Blagosklonny MV (ed.). "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.
  16. ↑ Nguyen D, Krueger BJ, Sedore SC, Brogie JE, Rogers JT, Rajendra TK, et al. (July 2012). "The Drosophila 7SK snRNP and the essential role of dHEXIM in development". Nucleic Acids Research. 40 (12): 5283–97. doi:10.1093/nar/gks191. PMC   3384314 . PMID   22379134.
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