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PMID: 17934474 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

prp8 mutations that cause human retinitis pigmentosa lead to a U5 snRNP maturation defect in yeast.

Nature structural & molecular biology ·Vol. 14 ·No. 11 ·2007-11-00 ·Pages 1077-83

Boon KL, Grainger RJ, Ehsani P, Barrass JD, Auchynnikava T, Inglehearn CF, Beggs JD

Abstract

Prp8 protein (Prp8p) is a highly conserved pre-mRNA splicing factor and a component of spliceosomal U5 small nuclear ribonucleoproteins (snRNPs). Although it is ubiquitously expressed, mutations in the C terminus of human Prp8p cause the retina-specific disease retinitis pigmentosa (RP). The biogenesis of U5 snRNPs is poorly characterized. We present evidence for a cytoplasmic precursor U5 snRNP in yeast that lacks the mature U5 snRNP component Brr2p and depends on a nuclear localization signal in Prp8p for its efficient nuclear import. The association of Brr2p with the U5 snRNP occurs within the nucleus. RP mutations in Prp8p in yeast result in nuclear accumulation of the precursor U5 snRNP, apparently as a consequence of disrupting the interaction of Prp8p with Brr2p. We therefore propose a novel assembly pathway for U5 snRNP complexes that is disrupted by mutations that cause human RP.

MeSH Terms
Humans In Situ Hybridization Macromolecular Substances/metabolism Mutation Nuclear Localization Signals Nuclear Proteins/genetics,metabolism RNA Helicases Recombinant Fusion Proteins/genetics,metabolism Repressor Proteins/genetics,metabolism Retinitis Pigmentosa/metabolism Ribonucleoprotein, U4-U6 Small Nuclear Ribonucleoprotein, U5 Small Nuclear/genetics,metabolism Saccharomyces cerevisiae/genetics,metabolism Saccharomyces cerevisiae Proteins/chemistry,genetics,metabolism
Chemicals
Aar2p protein, S cerevisiae Macromolecular Substances Nuclear Localization Signals Nuclear Proteins PRP8 protein, S cerevisiae Recombinant Fusion Proteins Repressor Proteins Ribonucleoprotein, U4-U6 Small Nuclear Ribonucleoprotein, U5 Small Nuclear Saccharomyces cerevisiae Proteins BRR2 protein, S cerevisiae RNA Helicases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Boon Kum-Loong
Wellcome Trust Centre for Cell Biology, University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, UK.
Grainger Richard J
Ehsani Parastoo
Barrass J David
Auchynnikava Tatsiana
Inglehearn Chris F
Beggs Jean D
References (45)
45 references, click to expand
  1. Monitoring communications between photoreceptors and pigment epithelial cells: effects of "mild" systemic hypoxia. Friedenwald lecture.
    Invest Ophthalmol Vis Sci. 1987 Dec;28(12):1888-904 PMID: 3316105
  2. The human U5-220kD protein (hPrp8) forms a stable RNA-free complex with several U5-specific proteins, including an RNA unwindase, a homologue of ribosomal elongation factor EF-2, and a novel WD-40 protein.
    Mol Cell Biol. 1998 Nov;18(11):6756-66 PMID: 9774689
  3. Spliceosomal UsnRNP biogenesis, structure and function.
    Curr Opin Cell Biol. 2001 Jun;13(3):290-301 PMID: 11343899
  4. Mutagenesis suggests several roles of Snu114p in pre-mRNA splicing.
    J Biol Chem. 2003 Jul 25;278(30):28324-34 PMID: 12736260
  5. Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13).
    Hum Mol Genet. 2001 Jul 15;10(15):1555-62 PMID: 11468273
  6. Functional characterization of nuclear localization signals in yeast Sm proteins.
    Mol Cell Biol. 2000 Nov;20(21):7943-54 PMID: 11027265
  7. Molecular genetics of autosomal dominant retinitis pigmentosa (ADRP): a comprehensive study of 43 Italian families.
    J Med Genet. 2005 Jul;42(7):e47 PMID: 15994872
  8. Why do cells need an assembly machine for RNA-protein complexes?
    Trends Cell Biol. 2004 May;14(5):226-32 PMID: 15130578
  9. The snoRNA box C/D motif directs nucleolar targeting and also couples snoRNA synthesis and localization.
    EMBO J. 1998 Jul 1;17(13):3747-57 PMID: 9649444
  10. Diversity in the signals required for nuclear accumulation of U snRNPs and variety in the pathways of nuclear transport.
    J Cell Biol. 1991 May;113(4):705-14 PMID: 1827444
  11. Prp8 protein: at the heart of the spliceosome.
    RNA. 2005 May;11(5):533-57 PMID: 15840809
  12. The human Prp8 protein is a component of both U2- and U12-dependent spliceosomes.
    RNA. 1999 Jul;5(7):893-908 PMID: 10411133
  13. Pre-mRNA splicing: awash in a sea of proteins.
    Mol Cell. 2003 Jul;12(1):5-14 PMID: 12887888
  14. Assembly and traffic of small nuclear RNPs.
    Prog Mol Subcell Biol. 2004;35:79-97 PMID: 15113080
  15. Structure of a multipartite protein-protein interaction domain in splicing factor prp8 and its link to retinitis pigmentosa.
    Mol Cell. 2007 Feb 23;25(4):615-24 PMID: 17317632
  16. Biochemical and genetic analyses of the U5, U6, and U4/U6 x U5 small nuclear ribonucleoproteins from Saccharomyces cerevisiae.
    RNA. 2001 Nov;7(11):1543-53 PMID: 11720284
  17. Snurportin1, an m3G-cap-specific nuclear import receptor with a novel domain structure.
    EMBO J. 1998 Jul 15;17(14):4114-26 PMID: 9670026
  18. PHAX, a mediator of U snRNA nuclear export whose activity is regulated by phosphorylation.
    Cell. 2000 Apr 14;101(2):187-98 PMID: 10786834
  19. Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa.
    Hum Mol Genet. 2002 Jan 1;11(1):87-92 PMID: 11773002
  20. Cloning of the RNA8 gene of Saccharomyces cerevisiae, detection of the RNA8 protein, and demonstration that it is essential for nuclear pre-mRNA splicing.
    Mol Cell Biol. 1988 Mar;8(3):1067-75 PMID: 2835658
  21. Yeast ntr1/spp382 mediates prp43 function in postspliceosomes.
    Mol Cell Biol. 2006 Aug;26(16):6016-23 PMID: 16880513
  22. Additional modules for versatile and economical PCR-based gene deletion and modification in Saccharomyces cerevisiae.
    Yeast. 1998 Jul;14(10):953-61 PMID: 9717241
  23. The U1 small nuclear ribonucleoprotein (snRNP) 70K protein is transported independently of U1 snRNP particles via a nuclear localization signal in the RNA-binding domain.
    Mol Cell Biol. 1994 Jul;14(7):4662-70 PMID: 7516470
  24. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11).
    Mol Cell. 2001 Aug;8(2):375-81 PMID: 11545739
  25. Prp8p dissection reveals domain structure and protein interaction sites.
    RNA. 2006 Feb;12(2):198-205 PMID: 16373487
  26. Assembly and localization of the U1-specific snRNP C protein in the amphibian oocyte.
    J Cell Biol. 1992 Dec;119(5):1037-46 PMID: 1447287
  27. The yeast U5 snRNP coisolated with the U1 snRNP has an unexpected protein composition and includes the splicing factor Aar2p.
    RNA. 2001 Nov;7(11):1554-65 PMID: 11720285
  28. Mutations in a protein target of the Pim-1 kinase associated with the RP9 form of autosomal dominant retinitis pigmentosa.
    Eur J Hum Genet. 2002 Apr;10(4):245-9 PMID: 12032732
  29. A three-dimensional view of precursor messenger RNA metabolism within the mammalian nucleus.
    Science. 1993 Feb 26;259(5099):1330-5 PMID: 8446902
  30. Diagnosis of autosomal dominant retinitis pigmentosa by linkage-based exclusion screening with multiple locus-specific microsatellite markers.
    Invest Ophthalmol Vis Sci. 2003 Mar;44(3):1275-81 PMID: 12601059
  31. Biogenesis of small nuclear RNPs.
    J Cell Sci. 2004 Dec 1;117(Pt 25):5949-51 PMID: 15564372
  32. A novel role for a U5 snRNP protein in 3' splice site selection.
    Genes Dev. 1995 Apr 1;9(7):855-68 PMID: 7535718
  33. Functional contacts with a range of splicing proteins suggest a central role for Brr2p in the dynamic control of the order of events in spliceosomes of Saccharomyces cerevisiae.
    Genetics. 2001 Apr;157(4):1451-67 PMID: 11290703
  34. Yeast mRNA splicing in vitro.
    J Biol Chem. 1985 Nov 25;260(27):14780-92 PMID: 2997224
  35. Clinical phenotype of an Italian family with a new mutation in the PRPF8 gene.
    Eur J Ophthalmol. 2006 Sep-Oct;16(5):779-81 PMID: 17061239
  36. PAP-1, the mutated gene underlying the RP9 form of dominant retinitis pigmentosa, is a splicing factor.
    Exp Cell Res. 2004 Nov 1;300(2):283-96 PMID: 15474994
  37. Pre-mRNA splicing and human disease.
    Genes Dev. 2003 Feb 15;17(4):419-37 PMID: 12600935
  38. A role for Cajal bodies in the final steps of U2 snRNP biogenesis.
    J Cell Sci. 2004 Sep 1;117(Pt 19):4423-33 PMID: 15316075
  39. An ATP-dependent, Ran-independent mechanism for nuclear import of the U1A and U2B" spliceosome proteins.
    J Cell Biol. 2000 Jan 24;148(2):293-303 PMID: 10648562
  40. Interaction of the U1 snRNP with nonconserved intronic sequences affects 5' splice site selection.
    Genes Dev. 1999 Mar 1;13(5):569-80 PMID: 10072385
  41. A diverse set of nuclear RNAs transfer between nuclei of yeast heterokaryons.
    Yeast. 2003 Jul 30;20(10):893-903 PMID: 12868058
  42. Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa.
    Invest Ophthalmol Vis Sci. 2003 May;44(5):2171-7 PMID: 12714658
  43. Green fluorescent protein as a marker for gene expression and subcellular localization in budding yeast.
    Yeast. 1996 Jun 30;12(8):773-86 PMID: 8813764
  44. Mutational analysis of pre-mRNA splicing in Saccharomyces cerevisiae using a sensitive new reporter gene, CUP1.
    Genetics. 1993 Apr;133(4):851-63 PMID: 8462846
  45. Identification and characterization of Prp45p and Prp46p, essential pre-mRNA splicing factors.
    RNA. 2003 Jan;9(1):138-50 PMID: 12554883
Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb1303
Published
2007-11-00
Epub
2007-00-14
Pages
1077-83
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC2584834
Subset
IM
Grants
Wellcome Trust · 067311 · United Kingdom
Wellcome Trust · 073988 · United Kingdom
External Links
PubMed source DOI: 10.1038/nsmb1303 PMC Full Text View journal details
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