title: Competition between pre-mRNAs for the splicing machinery drives global regulation of splicing.
abstract: During meiosis in yeast, global splicing efficiency increases and then decreases. Here we provide evidence that splicing improves due to reduced competition for the splicing machinery. The timing of this regulation corresponds to repression and reactivation of ribosomal protein genes (RPGs) during meiosis. In vegetative cells, RPG repression by rapamycin treatment also increases splicing efficiency. Downregulation of the RPG-dedicated transcription factor gene IFH1 genetically suppresses two spliceosome mutations, prp11-1 and prp4-1, and globally restores splicing efficiency in prp4-1 cells. We conclude that the splicing apparatus is limiting and that pre-messenger RNAs compete. Splicing efficiency of a pre-mRNA therefore depends not just on its own concentration and affinity for limiting splicing factor(s), but also on those of competing pre-mRNAs. Competition between RNAs for limiting processing factors appears to be a general condition in eukaryotes for a variety of posttranscriptional control mechanisms including microRNA (miRNA) repression, polyadenylation, and splicing.
authors.affiliation: Center for Molecular Biology of RNA, Department of Molecular, Cell & Developmental Biology, Sinsheimer Laboratories, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Munding
authors.forename: Lily
authors.initials: L
authors.lastname: Shiue
authors.forename: Sol
authors.initials: S
authors.lastname: Katzman
authors.forename: John Paul
authors.initials: JP
authors.lastname: Donohue
authors.forename: Manuel
authors.initials: M
authors.lastname: Ares
mesh_terms: D001483:Base Sequence; D015536:Down-Regulation; D008540:Meiosis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism*; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012332:RNA, Heterogeneous Nuclear / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000235:genetics; D012269:Ribosomal Proteins / Q000096:biosynthesis / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics; D017423:Sequence Analysis, RNA; D020123:Sirolimus / Q000494:pharmacology; D017381:Spliceosomes / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis; D014158:Transcription, Genetic
chemical_list: C094046:IFH1 protein, S cerevisiae; C068835:PRP11 protein, S cerevisiae; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D012331:RNA, Fungal; D012332:RNA, Heterogeneous Nuclear; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; C083212:PRP4 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus
references.citation: Nucleic Acids Res. 2000 Apr 15;28(8):1700-6
references.pmid: 10734188
references.citation: Microbiol Rev. 1994 Mar;58(1):56-70
references.pmid: 8177171
references.citation: Genetics. 2011 Nov;189(3):737-65
references.pmid: 22084423
references.citation: Cell. 1991 Sep 20;66(6):1257-68
references.pmid: 1840507
references.citation: Cell. 2011 Sep 30;147(1):132-46
references.pmid: 21924763
references.citation: PLoS Genet. 2007 Nov;3(11):e204
references.pmid: 18020710
references.citation: RNA. 2012 Jun;18(6):1103-15
references.pmid: 22539526
references.citation: Nat Genet. 2008 Dec;40(12):1413-5
references.pmid: 18978789
references.citation: Mol Biol Cell. 1999 Apr;10(4):987-1000
references.pmid: 10198052
references.citation: Bioinformatics. 2004 Jun 12;20(9):1453-4
references.pmid: 14871861
references.citation: Science. 2012 Dec 21;338(6114):1587-93
references.pmid: 23258890
references.citation: Genes Dev. 2010 Dec 1;24(23):2693-704
references.pmid: 21123654
references.citation: RNA. 2003 Aug;9(8):993-1006
references.pmid: 12869710
references.citation: RNA. 2004 Dec;10(12):1907-15
references.pmid: 15547136
references.citation: Mol Cell Biol. 2005 Nov;25(22):10005-16
references.pmid: 16260614
references.citation: Nature. 2010 Jun 24;465(7301):1033-8
references.pmid: 20577206
references.citation: J Comput Biol. 2004;11(2-3):377-94
references.pmid: 15285897
references.citation: Yeast. 1998 Jul;14(10):953-61
references.pmid: 9717241
references.citation: Science. 2012 Dec 21;338(6114):1593-9
references.pmid: 23258891
references.citation: J Biol Chem. 1995 Nov 17;270(46):27531-7
references.pmid: 7499212
references.citation: Annu Rev Biochem. 2003;72:291-336
references.pmid: 12626338
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14866-70
references.pmid: 10611304
references.citation: Mol Cell Biol. 2006 Jul;26(13):4853-62
references.pmid: 16782874
references.citation: Cell. 2011 Oct 14;147(2):358-69
references.pmid: 22000014
references.citation: Trends Genet. 2012 Apr;28(4):147-54
references.pmid: 22397991
references.citation: Bioinformatics. 2004 Nov 22;20(17):3246-8
references.pmid: 15180930
references.citation: RNA Biol. 2009 Nov-Dec;6(5):546-62
references.pmid: 19829082
references.citation: Genes Dev. 1994 Apr 1;8(7):796-810
references.pmid: 7926768
references.citation: Nature. 2004 Dec 23;432(7020):1054-8
references.pmid: 15616568
references.citation: Nucleic Acids Res. 1998 Dec 15;26(24):5568-72
references.pmid: 9837984
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12467-72
references.pmid: 9356473
references.citation: Mol Cell. 2004 Dec 22;16(6):929-41
references.pmid: 15610736
references.citation: Methods Enzymol. 1991;194:3-21
references.pmid: 2005794
references.citation: EMBO J. 1999 Oct 15;18(20):5714-23
references.pmid: 10523314
references.citation: Nat Genet. 2007 Aug;39(8):1033-7
references.pmid: 17643101
references.citation: Nature. 2008 Nov 27;456(7221):470-6
references.pmid: 18978772
references.citation: PLoS Biol. 2007 Apr;5(4):e90
references.pmid: 17388687
references.citation: EMBO J. 2003 Feb 17;22(4):905-12
references.pmid: 12574126
references.citation: Science. 1998 Oct 23;282(5389):699-705
references.pmid: 9784122
references.citation: RNA. 1999 Sep;5(9):1135-7
references.pmid: 10496213
references.citation: Cell. 2009 Sep 4;138(5):898-910
references.pmid: 19737518
references.citation: Nucleic Acids Res. 1993 Apr 11;21(7):1555-62
references.pmid: 8479905
references.citation: Science. 2003 Dec 12;302(5652):1978-80
references.pmid: 14671308
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20333-8
references.pmid: 19075228
references.citation: Bioinformatics. 2009 May 1;25(9):1105-11
references.pmid: 19289445
references.citation: EMBO J. 2000 Sep 1;19(17):4439-48
references.pmid: 10970838
references.citation: Nature. 2010 Jan 28;463(7280):457-63
references.pmid: 20110989
references.citation: Cold Spring Harb Protoc. 2012 Oct 01;2012(10):1082-6
references.pmid: 23028070
references.citation: Genome Biol. 2010;11(8):R87
references.pmid: 20796282
references.citation: Nature. 2010 Dec 2;468(7324):664-8
references.pmid: 20881964
references.citation: Cell. 2011 Aug 5;146(3):353-8
references.pmid: 21802130
references.citation: Nat Methods. 2012 Mar 04;9(4):357-9
references.pmid: 22388286
references.citation: Cell. 1998 Nov 25;95(5):717-28
references.pmid: 9845373
references.citation: Genes Dev. 1993 Oct;7(10):1909-25
references.pmid: 8405998
references.citation: Neuron. 1993 Oct;11(4):657-72
references.pmid: 8398153
references.citation: Cold Spring Harb Perspect Biol. 2011 Jul 01;3(7):
references.pmid: 21441581
references.citation: RNA. 2008 Aug;14(8):1463-9
references.pmid: 18579871
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1522-7
references.pmid: 17244705
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13431-6
references.pmid: 12370439
references.citation: Mol Biol Cell. 2000 Dec;11(12):4241-57
references.pmid: 11102521
references.citation: Nat Struct Mol Biol. 2009 Feb;16(2):130-7
references.pmid: 19136955
references.citation: J Bacteriol. 1967 May;93(5):1662-70
references.pmid: 5337848
references.citation: Nat Struct Mol Biol. 2005 Feb;12(2):175-82
references.pmid: 15702072
references.citation: Mol Cell. 2012 Oct 26;48(2):219-30
references.pmid: 22959273
references.citation: Mol Cell. 2008 Aug 8;31(3):360-70
references.pmid: 18691968
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14548-53
references.pmid: 11114178
references.citation: Genes Dev. 1991 Dec;5(12A):2303-14
references.pmid: 1748286
references.citation: Mol Cell Biol. 2000 Oct;20(20):7463-79
references.pmid: 11003644
references.citation: Mol Cell. 2003 Aug;12(2):525-32
references.pmid: 14536091
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):5860-5
references.pmid: 11972065
references.citation: Curr Opin Cell Biol. 2005 Jun;17(3):262-8
references.pmid: 15901495
references.citation: Genetics. 1994 Mar;136(3):833-47
references.pmid: 8005438
references.citation: Genes Dev. 1999 Dec 15;13(24):3271-9
references.pmid: 10617575
references.citation: RNA. 1999 Sep;5(9):1138-9
references.pmid: 10496214
references.citation: Cell. 2012 Jul 6;150(1):53-64
references.pmid: 22770214
references.citation: Yeast. 1997 Sep 15;13(11):1065-75
references.pmid: 9290211
references.citation: Genes Dev. 2007 Jul 1;21(13):1636-52
references.pmid: 17606642
references.citation: RNA. 2005 May;11(5):683-98
references.pmid: 15840817
references.citation: Science. 2002 May 3;296(5569):907-10
references.pmid: 11988574
references.citation: Science. 1991 Aug 23;253(5022):905-9
references.pmid: 1715094
references.citation: Nat Struct Mol Biol. 2010 Feb;17(2):187-93
references.pmid: 20098426
references.citation: Trends Biochem Sci. 1999 Nov;24(11):437-40
references.pmid: 10542411
references.citation: Mol Syst Biol. 2011 Dec 20;7:561
references.pmid: 22186735
references.citation: Nat Genet. 2000 Dec;26(4):415-23
references.pmid: 11101837
references.citation: Nature. 2004 Dec 23;432(7020):1058-61
references.pmid: 15616569
references.citation: Genetics. 1993 Apr;133(4):851-63
references.pmid: 8462846
references.citation: Nat Rev Genet. 2011 Sep 16;12(10):715-29
references.pmid: 21921927
references.citation: Cell. 2004 Dec 29;119(7):969-79
references.pmid: 15620355
references.citation: EMBO J. 2005 Feb 9;24(3):533-42
references.pmid: 15692568
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15974-9
references.pmid: 15492211
references.citation: Mol Cell Biol. 2005 Dec;25(23):10251-60
references.pmid: 16287842
references.citation: Mol Cell Biol. 1999 Aug;19(8):5393-404
references.pmid: 10409730
references.citation: PLoS Comput Biol. 2006 Jan;2(1):e4
references.pmid: 16424921