Skip to main content
PMC home page
RNA logoLink to RNA
. 2001 Dec;7(12):1693–1701.

A genome-wide survey of RS domain proteins.

L Boucher 1, C A Ouzounis 1, A J Enright 1, B J Blencowe 1
PMCID: PMC1370209  PMID: 11780626

Abstract

Domains rich in alternating arginine and serine residues (RS domains) are frequently found in metazoan proteins involved in pre-mRNA splicing. The RS domains of splicing factors associate with each other and are important for the formation of protein-protein interactions required for both constitutive and regulated splicing. The prevalence of the RS domain in splicing factors suggests that it might serve as a useful signature for the identification of new proteins that function in pre-mRNA processing, although it remains to be determined whether RS domains also participate in other cellular functions. Using database search and sequence clustering methods, we have identified and categorized RS domain proteins encoded within the entire genomes of Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae. This genome-wide survey revealed a surprising complexity of RS domain proteins in metazoans with functions associated with chromatin structure, transcription by RNA polymerase II, cell cycle, and cell structure, as well as pre-mRNA processing. Also identified were RS domain proteins in S. cerevisiae with functions associated with cell structure, osmotic regulation, and cell cycle progression. The results thus demonstrate an effective strategy for the genomic mining of RS domain proteins. The identification of many new proteins using this strategy has provided a database of factors that are candidates for forming RS domain-mediated interactions associated with different steps in pre-mRNA processing, in addition to other cellular functions.

Full Text

The Full Text of this article is available as a PDF (680.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aravind L., Koonin E. V. SAP - a putative DNA-binding motif involved in chromosomal organization. Trends Biochem Sci. 2000 Mar;25(3):112–114. doi: 10.1016/s0968-0004(99)01537-6. [DOI] [PubMed] [Google Scholar]
  2. Birney E., Kumar S., Krainer A. R. Analysis of the RNA-recognition motif and RS and RGG domains: conservation in metazoan pre-mRNA splicing factors. Nucleic Acids Res. 1993 Dec 25;21(25):5803–5816. doi: 10.1093/nar/21.25.5803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Black D. L. Protein diversity from alternative splicing: a challenge for bioinformatics and post-genome biology. Cell. 2000 Oct 27;103(3):367–370. doi: 10.1016/s0092-8674(00)00128-8. [DOI] [PubMed] [Google Scholar]
  4. Blencowe B. J., Bowman J. A., McCracken S., Rosonina E. SR-related proteins and the processing of messenger RNA precursors. Biochem Cell Biol. 1999;77(4):277–291. [PubMed] [Google Scholar]
  5. Blencowe B. J. Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem Sci. 2000 Mar;25(3):106–110. doi: 10.1016/s0968-0004(00)01549-8. [DOI] [PubMed] [Google Scholar]
  6. Cairns B. R., Henry N. L., Kornberg R. D. TFG/TAF30/ANC1, a component of the yeast SWI/SNF complex that is similar to the leukemogenic proteins ENL and AF-9. Mol Cell Biol. 1996 Jul;16(7):3308–3316. doi: 10.1128/mcb.16.7.3308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clotet J., Garí E., Aldea M., Ariño J. The yeast ser/thr phosphatases sit4 and ppz1 play opposite roles in regulation of the cell cycle. Mol Cell Biol. 1999 Mar;19(3):2408–2415. doi: 10.1128/mcb.19.3.2408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Colwill K., Pawson T., Andrews B., Prasad J., Manley J. L., Bell J. C., Duncan P. I. The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution. EMBO J. 1996 Jan 15;15(2):265–275. [PMC free article] [PubMed] [Google Scholar]
  9. Corden J. L., Patturajan M. A CTD function linking transcription to splicing. Trends Biochem Sci. 1997 Nov;22(11):413–416. doi: 10.1016/s0968-0004(97)01125-0. [DOI] [PubMed] [Google Scholar]
  10. Cramer P., Cáceres J. F., Cazalla D., Kadener S., Muro A. F., Baralle F. E., Kornblihtt A. R. Coupling of transcription with alternative splicing: RNA pol II promoters modulate SF2/ASF and 9G8 effects on an exonic splicing enhancer. Mol Cell. 1999 Aug;4(2):251–258. doi: 10.1016/s1097-2765(00)80372-x. [DOI] [PubMed] [Google Scholar]
  11. Cáceres J. F., Misteli T., Screaton G. R., Spector D. L., Krainer A. R. Role of the modular domains of SR proteins in subnuclear localization and alternative splicing specificity. J Cell Biol. 1997 Jul 28;138(2):225–238. doi: 10.1083/jcb.138.2.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Du C., McGuffin M. E., Dauwalder B., Rabinow L., Mattox W. Protein phosphorylation plays an essential role in the regulation of alternative splicing and sex determination in Drosophila. Mol Cell. 1998 Dec;2(6):741–750. doi: 10.1016/s1097-2765(00)80289-0. [DOI] [PubMed] [Google Scholar]
  13. Edwards M. C., Wong C., Elledge S. J. Human cyclin K, a novel RNA polymerase II-associated cyclin possessing both carboxy-terminal domain kinase and Cdk-activating kinase activity. Mol Cell Biol. 1998 Jul;18(7):4291–4300. doi: 10.1128/mcb.18.7.4291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Enright A. J., Ouzounis C. A. GeneRAGE: a robust algorithm for sequence clustering and domain detection. Bioinformatics. 2000 May;16(5):451–457. doi: 10.1093/bioinformatics/16.5.451. [DOI] [PubMed] [Google Scholar]
  15. Erez O., Kahana C. Screening for modulators of spermine tolerance identifies Sky1, the SR protein kinase of Saccharomyces cerevisiae, as a regulator of polyamine transport and ion homeostasis. Mol Cell Biol. 2001 Jan;21(1):175–184. doi: 10.1128/MCB.21.1.175-184.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fu X. D. The superfamily of arginine/serine-rich splicing factors. RNA. 1995 Sep;1(7):663–680. [PMC free article] [PubMed] [Google Scholar]
  17. Gilbert W., Siebel C. W., Guthrie C. Phosphorylation by Sky1p promotes Npl3p shuttling and mRNA dissociation. RNA. 2001 Feb;7(2):302–313. doi: 10.1017/s1355838201002369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Graveley B. R. Alternative splicing: increasing diversity in the proteomic world. Trends Genet. 2001 Feb;17(2):100–107. doi: 10.1016/s0168-9525(00)02176-4. [DOI] [PubMed] [Google Scholar]
  19. Graveley B. R. Sorting out the complexity of SR protein functions. RNA. 2000 Sep;6(9):1197–1211. doi: 10.1017/s1355838200000960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gui J. F., Lane W. S., Fu X. D. A serine kinase regulates intracellular localization of splicing factors in the cell cycle. Nature. 1994 Jun 23;369(6482):678–682. doi: 10.1038/369678a0. [DOI] [PubMed] [Google Scholar]
  21. Hedley M. L., Amrein H., Maniatis T. An amino acid sequence motif sufficient for subnuclear localization of an arginine/serine-rich splicing factor. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11524–11528. doi: 10.1073/pnas.92.25.11524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hirose Y., Manley J. L. RNA polymerase II and the integration of nuclear events. Genes Dev. 2000 Jun 15;14(12):1415–1429. [PubMed] [Google Scholar]
  23. Holtzman D. A., Yang S., Drubin D. G. Synthetic-lethal interactions identify two novel genes, SLA1 and SLA2, that control membrane cytoskeleton assembly in Saccharomyces cerevisiae. J Cell Biol. 1993 Aug;122(3):635–644. doi: 10.1083/jcb.122.3.635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Horowitz D. S., Kobayashi R., Krainer A. R. A new cyclophilin and the human homologues of yeast Prp3 and Prp4 form a complex associated with U4/U6 snRNPs. RNA. 1997 Dec;3(12):1374–1387. [PMC free article] [PubMed] [Google Scholar]
  25. Hsieh J. J., Zhou S., Chen L., Young D. B., Hayward S. D. CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):23–28. doi: 10.1073/pnas.96.1.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Huang Y., Deng T., Winston B. W. Characterization of hPRP4 kinase activation: potential role in signaling. Biochem Biophys Res Commun. 2000 May 10;271(2):456–463. doi: 10.1006/bbrc.2000.2651. [DOI] [PubMed] [Google Scholar]
  27. Kaplan C. D., Morris J. R., Wu C., Winston F. Spt5 and spt6 are associated with active transcription and have characteristics of general elongation factors in D. melanogaster. Genes Dev. 2000 Oct 15;14(20):2623–2634. doi: 10.1101/gad.831900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kasof G. M., Goyal L., White E. Btf, a novel death-promoting transcriptional repressor that interacts with Bcl-2-related proteins. Mol Cell Biol. 1999 Jun;19(6):4390–4404. doi: 10.1128/mcb.19.6.4390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Krauss S. W., Larabell C. A., Lockett S., Gascard P., Penman S., Mohandas N., Chasis J. A. Structural protein 4.1 in the nucleus of human cells: dynamic rearrangements during cell division. J Cell Biol. 1997 Apr 21;137(2):275–289. doi: 10.1083/jcb.137.2.275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Krämer A. The structure and function of proteins involved in mammalian pre-mRNA splicing. Annu Rev Biochem. 1996;65:367–409. doi: 10.1146/annurev.bi.65.070196.002055. [DOI] [PubMed] [Google Scholar]
  31. Lallena M. J., Martínez C., Valcárcel J., Correas I. Functional association of nuclear protein 4.1 with pre-mRNA splicing factors. J Cell Sci. 1998 Jul 30;111(Pt 14):1963–1971. doi: 10.1242/jcs.111.14.1963. [DOI] [PubMed] [Google Scholar]
  32. Lawrence J. B., Carter K. C., Xing X. Probing functional organization within the nucleus: is genome structure integrated with RNA metabolism? Cold Spring Harb Symp Quant Biol. 1993;58:807–818. doi: 10.1101/sqb.1993.058.01.088. [DOI] [PubMed] [Google Scholar]
  33. Li H., Bingham P. M. Arginine/serine-rich domains of the su(wa) and tra RNA processing regulators target proteins to a subnuclear compartment implicated in splicing. Cell. 1991 Oct 18;67(2):335–342. doi: 10.1016/0092-8674(91)90185-2. [DOI] [PubMed] [Google Scholar]
  34. Lin P., Huang L. H., Steward R. Cactin, a conserved protein that interacts with the Drosophila IkappaB protein cactus and modulates its function. Mech Dev. 2000 Jun;94(1-2):57–65. doi: 10.1016/s0925-4773(00)00314-2. [DOI] [PubMed] [Google Scholar]
  35. Longman D., Johnstone I. L., Cáceres J. F. Functional characterization of SR and SR-related genes in Caenorhabditis elegans. EMBO J. 2000 Apr 3;19(7):1625–1637. doi: 10.1093/emboj/19.7.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Manley J. L., Tacke R. SR proteins and splicing control. Genes Dev. 1996 Jul 1;10(13):1569–1579. doi: 10.1101/gad.10.13.1569. [DOI] [PubMed] [Google Scholar]
  37. Misteli T., Spector D. L. The cellular organization of gene expression. Curr Opin Cell Biol. 1998 Jun;10(3):323–331. doi: 10.1016/s0955-0674(98)80007-0. [DOI] [PubMed] [Google Scholar]
  38. Mount S. M., Salz H. K. Pre-messenger RNA processing factors in the Drosophila genome. J Cell Biol. 2000 Jul 24;150(2):F37–F44. doi: 10.1083/jcb.150.2.f37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nayler O., Strätling W., Bourquin J. P., Stagljar I., Lindemann L., Jasper H., Hartmann A. M., Fackelmayer F. O., Ullrich A., Stamm S. SAF-B protein couples transcription and pre-mRNA splicing to SAR/MAR elements. Nucleic Acids Res. 1998 Aug 1;26(15):3542–3549. doi: 10.1093/nar/26.15.3542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Ogiwara A., Uchiyama I., Takagi T., Kanehisa M. Construction and analysis of a profile library characterizing groups of structurally known proteins. Protein Sci. 1996 Oct;5(10):1991–1999. doi: 10.1002/pro.5560051005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Preker P. J., Lingner J., Minvielle-Sebastia L., Keller W. The FIP1 gene encodes a component of a yeast pre-mRNA polyadenylation factor that directly interacts with poly(A) polymerase. Cell. 1995 May 5;81(3):379–389. doi: 10.1016/0092-8674(95)90391-7. [DOI] [PubMed] [Google Scholar]
  42. Promponas V. J., Enright A. J., Tsoka S., Kreil D. P., Leroy C., Hamodrakas S., Sander C., Ouzounis C. A. CAST: an iterative algorithm for the complexity analysis of sequence tracts. Complexity analysis of sequence tracts. Bioinformatics. 2000 Oct;16(10):915–922. doi: 10.1093/bioinformatics/16.10.915. [DOI] [PubMed] [Google Scholar]
  43. Rando O. J., Zhao K., Crabtree G. R. Searching for a function for nuclear actin. Trends Cell Biol. 2000 Mar;10(3):92–97. doi: 10.1016/s0962-8924(99)01713-4. [DOI] [PubMed] [Google Scholar]
  44. Roscigno R. F., Garcia-Blanco M. A. SR proteins escort the U4/U6.U5 tri-snRNP to the spliceosome. RNA. 1995 Sep;1(7):692–706. [PMC free article] [PubMed] [Google Scholar]
  45. Russell P., Moreno S., Reed S. I. Conservation of mitotic controls in fission and budding yeasts. Cell. 1989 Apr 21;57(2):295–303. doi: 10.1016/0092-8674(89)90967-7. [DOI] [PubMed] [Google Scholar]
  46. Rüegsegger U., Blank D., Keller W. Human pre-mRNA cleavage factor Im is related to spliceosomal SR proteins and can be reconstituted in vitro from recombinant subunits. Mol Cell. 1998 Jan;1(2):243–253. doi: 10.1016/s1097-2765(00)80025-8. [DOI] [PubMed] [Google Scholar]
  47. Sahara S., Aoto M., Eguchi Y., Imamoto N., Yoneda Y., Tsujimoto Y. Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation. Nature. 1999 Sep 9;401(6749):168–173. doi: 10.1038/43678. [DOI] [PubMed] [Google Scholar]
  48. Sia R. A., Herald H. A., Lew D. J. Cdc28 tyrosine phosphorylation and the morphogenesis checkpoint in budding yeast. Mol Biol Cell. 1996 Nov;7(11):1657–1666. doi: 10.1091/mbc.7.11.1657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Siebel C. W., Feng L., Guthrie C., Fu X. D. Conservation in budding yeast of a kinase specific for SR splicing factors. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5440–5445. doi: 10.1073/pnas.96.10.5440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Smith C. W., Valcárcel J. Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem Sci. 2000 Aug;25(8):381–388. doi: 10.1016/s0968-0004(00)01604-2. [DOI] [PubMed] [Google Scholar]
  51. Spector D. L. Macromolecular domains within the cell nucleus. Annu Rev Cell Biol. 1993;9:265–315. doi: 10.1146/annurev.cb.09.110193.001405. [DOI] [PubMed] [Google Scholar]
  52. Stojdl D. F., Bell J. C. SR protein kinases: the splice of life. Biochem Cell Biol. 1999;77(4):293–298. [PubMed] [Google Scholar]
  53. Stroumbakis N. D., Li Z., Tolias P. P. A homolog of human transcription factor NF-X1 encoded by the Drosophila shuttle craft gene is required in the embryonic central nervous system. Mol Cell Biol. 1996 Jan;16(1):192–201. doi: 10.1128/mcb.16.1.192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Suñ C., Hayashi T., Liu Y., Lane W. S., Young R. A., Garcia-Blanco M. A. CA150, a nuclear protein associated with the RNA polymerase II holoenzyme, is involved in Tat-activated human immunodeficiency virus type 1 transcription. Mol Cell Biol. 1997 Oct;17(10):6029–6039. doi: 10.1128/mcb.17.10.6029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Takeuchi M., Yanagida M. A mitotic role for a novel fission yeast protein kinase dsk1 with cell cycle stage dependent phosphorylation and localization. Mol Biol Cell. 1993 Mar;4(3):247–260. doi: 10.1091/mbc.4.3.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Teigelkamp S., Achsel T., Mundt C., Göthel S. F., Cronshagen U., Lane W. S., Marahiel M., Lührmann R. The 20kD protein of human [U4/U6.U5] tri-snRNPs is a novel cyclophilin that forms a complex with the U4/U6-specific 60kD and 90kD proteins. RNA. 1998 Feb;4(2):127–141. [PMC free article] [PubMed] [Google Scholar]
  57. Wada T., Takagi T., Yamaguchi Y., Ferdous A., Imai T., Hirose S., Sugimoto S., Yano K., Hartzog G. A., Winston F. DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev. 1998 Feb 1;12(3):343–356. doi: 10.1101/gad.12.3.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Welch M. D., Drubin D. G. A nuclear protein with sequence similarity to proteins implicated in human acute leukemias is important for cellular morphogenesis and actin cytoskeletal function in Saccharomyces cerevisiae. Mol Biol Cell. 1994 Jun;5(6):617–632. doi: 10.1091/mbc.5.6.617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Xiao S. H., Manley J. L. Phosphorylation-dephosphorylation differentially affects activities of splicing factor ASF/SF2. EMBO J. 1998 Nov 2;17(21):6359–6367. doi: 10.1093/emboj/17.21.6359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yeakley J. M., Tronchère H., Olesen J., Dyck J. A., Wang H. Y., Fu X. D. Phosphorylation regulates in vivo interaction and molecular targeting of serine/arginine-rich pre-mRNA splicing factors. J Cell Biol. 1999 May 3;145(3):447–455. doi: 10.1083/jcb.145.3.447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Yun C. Y., Fu X. D. Conserved SR protein kinase functions in nuclear import and its action is counteracted by arginine methylation in Saccharomyces cerevisiae. J Cell Biol. 2000 Aug 21;150(4):707–718. doi: 10.1083/jcb.150.4.707. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from RNA are provided here courtesy of The RNA Society

RESOURCES