Small Nuclear Ribonucleoproteins (snRNPs)

Abstract

Small nuclear ribonucleoproteins (snRNPs) are protein–ribonucleic acid (RNA) complexes defined by a core noncoding RNA of approximately 100–600 nucleotides and tightly bound proteins that together accumulate in the nucleus. The snRNPs are best known for their role in RNA splicing complexes, including U1, U2, U4, U5 and U6 snRNPs found in the spliceosome. Additional snRNPs are functionally diverse, but in many cases the RNA component of snRNPs can base‐pair with a substrate for precise alignment and possible catalysis. The U7 snRNP directs 3′‐end mRNA formation for histone transcripts, and the 7SK snRNP regulates transcription. Two special groups of snRNPs, small nucleolar RNPs (snoRNPs) and small Cajal‐body RNPs (scaRNPs), are restricted to their named subnuclear compartments in order to direct post‐transcriptional modification of ribosomal and splicing RNAs, respectively. Certain herpesviruses express high levels of novel snRNPs involved in the regulation of gene expression. Due to their important biological roles, there are many diseases associated with snRNPs.

Key Concepts:

  • The snRNPs are small nuclear ribonucleoprotein particles, a class of dynamic RNA–protein complexes that accumulate in the nucleus.

  • Major and minor splicing snRNPs form super‐complexes (spliceosomes) that direct the precise splicing of messenger RNAs.

  • In the special process of trans‐splicing, splice leader (SL) snRNPs donate RNA to the ends of transcripts.

  • The U7 snRNP coordinates 3′ end processing of metazoan histone messenger RNAs.

  • The 7SK snRNP regulates transcription by selectively sequestering and rendering inactive the P‐TEFb protein, a key modulator of RNA polymerase II.

  • Two groups of snRNPs are singled out for specific subnuclear localisation: small nucleolar and small Cajal‐body associated (sno/scaRNPs) direct methylation and pseudouridylation of splicing and ribosomal RNAs.

  • Some mammalian herpesviruses express viral snRNPs, which have enigmatic and complex functions in gene regulation.

  • Several diseases including lupus present autoantibody production of antibodies directed at snRNP‐affiliated proteins such as Sm, Lsm and La.

  • Most snRNPs have been affiliated with diseases and are therefore promising biomarkers for diagnosis and prognosis.

Keywords: mRNA splicing; splice leader RNA; snoRNA; scaRNA; U7; 7SK; EBER; HSUR; viral snRNPs; lupus

Figure 1.

Secondary structural features of the U1 and U11 snRNAs are similar. (a) Secondary structural predictions indicate a remarkably similar overall four‐hairpin fold for both U1 and U11 in spite of extensive differences in primary sequence. The 5′ splice site (red boxes) and Sm protein (black boxes) binding sequences are in approximately the same place in both RNAs. The consensus sequence for Sm protein binding is noted on U1. (b) Both snRNAs have a 5′ TMG cap (depicted as a triangle in (a)).

Figure 2.

Schematic representation of the U7 snRNP directing histone mRNA 3′ end formation. The U7 snRNA has a 5′ TMG cap (triangle) and Sm/Lsm protein ring (light blue). Stem‐loop binding protein (SLBP) binds a specific hairpin near the 3′ end of the histone mRNA (purple) and interacts with the zinc finger protein (ZFP100) bridging protein (green), which also binds Lsm11 (light blue). A region of the U7 snRNA known as the HDE base‐pairs to the histone pre‐mRNA substrate (red box). The histone mRNA is cleaved in the denoted location (red arrow), for which the CPSF‐73 endonuclease is required (dark blue).

Figure 3.

Cartoon structure of the human 7SK snRNA based on a model for structural pairing predicted by conservation of primary sequences across many species. Coloured areas highlight portions of the snRNA that directly or indirectly facilitate protein binding in the snRNP. A large stem loop is the binding site for the HEXIM proteins (blue). To be fully associated with 7SK snRNP, P‐TEFb requires a hairpin near the 3′ end of the snRNA (purple) and makes key protein–protein contacts with HEXIM. The 3′ end (yellow) is comprised of a stretch of uridine residues that are initially bound by the La protein, which is replaced by Larp7 after post‐transcriptional modifications of the end. MePCE methylates the 5′ end of the 7SK snRNA (green). When P‐TEFb and HEXIM dissociate from the 7SK snRNP complex, they are replaced by heterogeneous RNP particle (hnRNP) proteins, which bind in two regions (open circles), including a stretch of seven base pairs that anchors the 5′ end near the 3′ end (Peterlin et al., ; Marz et al., ).

Figure 4.

Chemical modifications of RNA directed by snoRNAs. (a) The process of 2′‐O‐ribose methylation of RNA is the addition of a methyl group (red) via the oxygen connected to the 2′ ribose carbon of a specific nucleotide (attached phosphate groups and bases remain unaltered). (b) Pseudouridylation is the isomerisation of uracil into pseudouracil while the sugar/phosphate backbone remains unchanged. Altered chemical substituents are highlighted (red). (c) Schematic secondary structure of a representative class C/D snoRNA, which contains class‐specific conserved sequences (boxes C and D, blue and green). Unique guide sequences base‐pair with target rRNAs (red). A methyl group is added to the rRNA residue base‐paired to the fifth position upstream from box D or D’. (d) Box H/ACA snoRNAs adopt a double hairpin structure. Base‐pairing of an rRNA to an internal loop in the snoRNA results in the pseudouridylation (Nψ) of an unpaired rRNA U residue (usually 14–16 nucleotides from the H or ACA box).

Figure 5.

Viral snRNPs. (a) The predicted secondary structures of EBV EBERs 1 and 2 depict hairpins, some of which are binding sites for proteins. Ribosomal protein pRL22 binds to three of the stem loops in EBER1 (green). The La protein binds a U‐rich track in both EBERs (purple). The PKR protein (in vitro) and nucleolin have been shown to bind EBERs 1 and 2, respectively, though their binding sites have not been mapped. (b) HSUR1 is one of the seven snRNAs expressed in H. saimiri. The HSUR1 snRNP has a 5′ TMG cap (triangle) and includes a ring of host Sm proteins (light blue). HSUR1 base‐pairs to two human microRNAs (miR‐27 and miR‐142‐3p) in the locations shown (yellow).

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References

Berget SM, Moore C and Sharp PA (1977) Splice segments at the 5′ terminus of adenovirus 2 late mRNA. Proceedings of the National Academy of Sciences of the USA 74(8): 3171–3175.

Cazalla D, Yario T and Steitz JA (2010) Down‐regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science 328(5985): 1563–1566.

Chow LT, Gelinas RE, Broker TR and Roberts RJ (1977) An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA. Cell 12(1): 1–8.

Darzacq X, Jady BE, Verheggen C et al. (2002) Cajal body‐specific small nuclear RNAs: a novel class of 2′‐O‐methylation and pseudouridylation guide RNAs. EMBO Journal 21(11): 2746–2756.

Diribarne G and Bensaude O (2009) 7SK RNA, a non‐coding RNA regulating P‐TEFb, a general transcription factor. RNA Biology 6(2): 122–128.

Evans D and Blumenthal T (2000) trans Splicing of polycistronic Caenorhabditis elegans pre‐mRNAs: analysis of the SL2 RNA. Molecular and Cellular Biology 20(18): 6659–6667.

Galej WP, Oubridge C, Newman AJ and Nagai K (2013) Crystal structure of Prp8 reveals active site cavity of the spliceosome. Nature 493(7434): 638–643.

Guo YE, Riley KJ, Iwasaki A and Steitz JA (2014) Alternative capture of noncoding RNAs or protein‐coding genes by herpesviruses to alter host T cell function. Molecular Cell 54(1): 67–79.

Jády BE and Kiss T (2001) A small nucleolar guide RNA functions both in 2′‐O‐ribose methylation and pseudouridylation of the U5 spliceosomal RNA. EMBO Journal 20(3): 541–551.

Jeronimo C, Forget D, Bouchard A et al. (2007) Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular Cell 27: 262–274.

Krueger BJ, Jeronimo C, Roy BB et al. (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): 2219–2229.

Lapinaite A, Simon B, Skjaerven L et al. (2013) The structure of the box C/D enzyme reveals regulation of RNA methylation. Nature 502(7472): 519–523.

Lee N, Pimienta G and Steitz JA (2012) AUF1/hnRNP D is a novel protein partner of the EBER1 RNA of Epstein‐Barr virus. RNA 18(11): 2073–2082.

Lee SI, Murthy SCS, Trimble JJ, Desrosiers RC and Steitz JA (1988) Four novel U RNAs are encoded by a herpesvirus. Cell 54(5): 599–607.

Lerner MR, Andrews NC, Miller G and Steitz JA (1981) Two small RNAs encoded by Epstein‐Barr virus and complexed with protein are precipitated by antibodies from patients with systemic lupus erythematosus. Proceedings of the National Academy of Sciences of the USA 78: 805–809.

Lerner MR, Boyle JA, Mount SM, Wolin SL and Steitz JA (1980) Are snRNPs involved in splicing? Nature 283(5743): 220–224.

Lerner MR and Steitz JA (1979) Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus. Proceedings of the National Academy of Sciences of the USA 76(11): 5495–5499.

Leung AKW, Nagai K and Li J (2011) Structure of the spliceosomal U4 snRNP core domain and its implication for snRNP biogenesis. Nature 473(7348): 536–539.

Machyna M, Heyn P and Neugebauer KM (2013) Cajal bodies: where form meets function. Wiley Interdisciplinary Reviews: RNA 4(1): 17–34.

Mandel CR, Kaneko S, Zhang H et al. (2006) Polyadenylation factor CPSF‐73 is the pre‐mRNA 3′‐end‐processing endonuclease. Nature 444(7121): 953–956.

Marz M, Donath A, Verstraete N et al. (2009) Evolution of 7SK RNA and its protein partners in metazoa. Molecular Biology and Evolution 26(12): 2821–2830.

Mason PJ and Bessler M (2013) Poikiloderma with neutropenia: beginning at the end. Blood 121(6): 872–874.

Michels AA, Fraldi A, Li Q et al. (2004) Binding of the 7SK snRNA turns the HEXIM1 protein into a P‐TEFb (CDK9/cyclin T) inhibitor. EMBO Journal 23(13): 2608–2619.

Mowry KL and Steitz JA (1987) Identification of the human U7 snRNP as one of several factors involved in the 3′ end maturation of histone premessenger RNA's. Science 238 (4834): 1682–1687.

Mroczek S and Dziembowski A (2013) U6 RNA biogenesis and disease association. Wiley Interdisciplinary Reviews: RNA 4: 581–592.

Nguyen VT, Kiss T, Michels AA and Bensaude O (2001) 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 414(6861): 322–325.

Peterlin BM, Brogie JE and 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.

Pomeranz Krummel DA, Oubridge C, Leung AKW, Li J and Nagai K (2009) Crystal structure of human spliceosomal U1 snRNP at 5.5 Å resolution. Nature 458(7237): 475–480.

Reichow SL, Hamma T, Ferre‐D'Amare AR and Varani G (2007) The structure and function of small nucleolar ribonucleoproteins. Nucleic Acids Research 35(5): 1452–1464.

Richard P, Darzacq X, Bertrand E et al. (2003) A common sequence motif determines the Cajal body‐specific localization of box H/ACA scaRNAs. EMBO Journal 22(16): 4027–4336.

Ronchetti D, Mosca L, Cutrona G et al. (2013) Small nucleolar RNAs as new biomarkers in chronic lymphocytic leukemia. BMC Medical Genomics 6: 27.

Russell AG, Charette JM, Spencer DF and Gray MW (2006) An early evolutionary origin for the minor spliceosome. Nature 443: 863–866.

Steitz J, Borah S, Cazalla D et al. (2011) Noncoding RNPs of viral origin. Cold Spring Harbor Perspectives in Biology 3(3): 1–15.

Tarn WY and Steitz JA (1996) A novel spliceosome containing U11, U12, and U5 snRNPs excises a minor class (AT–AC) intron in vitro. Cell 84(5): 801–811.

Tsuiji H, Iguchi Y, Furuya A et al. (2013) Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Molecular Medicine 5(2): 221–234.

Turunen JJ, Niemela EH, Verma B and Frilander M (2013) The significant other: splicing by the minor spliceosome. Wiley Interdisciplinary Reviews: RNA 4(1): 61–76.

Tycowski K, Aab A and Steitz JA (2004) Guide RNAs with 5′ caps and novel Box C/D snoRNA‐like domains for modification of snRNAs in metazoa. Current Biology 14: 1985–1995.

Tycowski KT, Shu MD, Kukoyi A and Steitz JA (2009) A conserved WD40 protein binds Cajal body localization signal of scaRNP particles. Molecular Cell 34(1): 47–57.

Tycowski KT, You ZH, Graham PJ and Steitz JA (1998) Modification of U6 spliceosomal RNA is guided by other small RNAs. Molecular Cell 2(5): 629–638.

Wagner EJ and Marzluff WF (2006) ZFP100, a component of the active U7 snRNP limiting for histone pre‐mRNA processing is required for entry into S phase. Molecular and Cellular Biology 26(17): 6702–6712.

Wassarman DA and Steitz JA (1991) Structural analyses of the 7SK ribonucleoprotein (RNP), the most abundant human small RNP of unknown function. Molecular Cell Biology 11: 3432–3445.

Weber G, Trowitzsch G, Kastner B, Luhrmann R and Wahl MC (2010) Functional organization of the Sm core in the crystal structure of human U1 snRNP. EMBO Journal 29: 4172–4184.

Xie J, Zhang M, Zhou T et al. (2007) Sno/scaRNAbase: a curated database for small nucleolar RNAs and Cajal body‐specific RNAs. Nucleic Acids Research 35: D183–D187.

Further Reading

Burge CB, Padgett RA and Sharp PA (1998) Evolutionary fates and origins of U12‐type introns. Molecular Cell 2(6): 773–785.

Cech TR and Steitz JA (2014) The noncoding RNA revolution – trashing old rules to forge new ones. Cell 157(1): 77–94.

Kiss T (2004) Biogenesis of small nuclear RNPs. Journal of Cell Science 117: 5949–5951.

Matera AG, Terns RM and Terns MP (2007) Non‐coding RNAs: lessons from the small nuclear and small nucleolar RNAs. Nature Reviews Molecular Cell Biology 8: 209–220.

Patel AA and Steitz JA (2003) Splicing double: insights from the second spliceosome. Nature Reviews Molecular Cell Biology 4: 960–970.

Watkins NJ and Bohnsack MT (2012) The box C/D and H/ACA snoRNPs: key players in the modification, processing and the dynamic folding of ribosomal RNA. Wiley Interdisciplinary Reviews: RNA 3(3): 397–414.

Will CL and Luhrmann R (2011) Spliceosome structure and function. Cold Spring Harbor Perspectives in Biology 3(7): 1–23.

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Stone, Lauren B, and Riley, Kasandra J(Aug 2014) Small Nuclear Ribonucleoproteins (snRNPs). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005038]