title: Degradation of YRA1 Pre-mRNA in the cytoplasm requires translational repression, multiple modular intronic elements, Edc3p, and Mex67p.
abstract: Intron-containing pre-mRNAs are normally retained and processed in the nucleus but are sometimes exported to the cytoplasm and degraded by the nonsense-mediated mRNA decay (NMD) pathway as a consequence of their inclusion of intronic in-frame termination codons. When shunted to the cytoplasm by autoregulated nuclear export, the intron-containing yeast YRA1 pre-mRNA evades NMD and is targeted by a cytoplasmic decay pathway mediated by the decapping activator Edc3p. Here, we have elucidated this transcript-specific decay mechanism, showing that Edc3p-mediated YRA1 pre-mRNA degradation occurs independently of translation and is controlled through five structurally distinct but functionally interdependent modular elements in the YRA1 intron. Two of these elements target the pre-mRNA as an Edc3p substrate and the other three mediate transcript-specific translational repression. Translational repression of YRA1 pre-mRNA also requires the heterodimeric Mex67p/Mtr2p general mRNA export receptor, but not Edc3p, and serves to enhance Edc3p substrate specificity by inhibiting the susceptibility of this pre-mRNA to NMD. Collectively, our data indicate that YRA1 pre-mRNA degradation is a highly regulated process that proceeds through translational repression, substrate recognition by Edc3p, recruitment of the Dcp1p/Dcp2p decapping enzyme, and activation of decapping.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Dong
authors.forename: Allan
authors.initials: A
authors.lastname: Jacobson
authors.forename: Feng
authors.initials: F
authors.lastname: He
mesh_terms: D003593:Cytoplasm / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D007438:Introns; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D039381:RNA Cap-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism*; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C488957:EDC3 protein, S cerevisiae; C106898:MEX67 protein, S cerevisiae; D026901:Membrane Transport Proteins; C480169:Mtr2 protein, S cerevisiae; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D039381:RNA Cap-Binding Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; C105887:YRA1 protein, S cerevisiae; C100868:DCP1 protein, S cerevisiae; C400572:DCP2 protein, S cerevisiae; D004722:Endoribonucleases
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7034-8
references.pmid: 8346213
references.citation: Science. 2002 Mar 22;295(5563):2262-4
references.pmid: 11910110
references.citation: Genetics. 2004 Feb;166(2):729-39
references.pmid: 15020463
references.citation: RNA. 2006 Oct;12(10):1810-6
references.pmid: 16912217
references.citation: Yeast. 2000 Jun 30;17(2):95-110
references.pmid: 10900456
references.citation: Nature. 2002 Jan 10;415(6868):141-7
references.pmid: 11805826
references.citation: Development. 2004 Dec;131(23):5849-57
references.pmid: 15525666
references.citation: Eur J Biochem. 1997 May 1;245(3):557-63
references.pmid: 9182990
references.citation: Genes Dev. 1995 Feb 15;9(4):437-54
references.pmid: 7883168
references.citation: Cell. 2004 Jan 9;116(1):63-73
references.pmid: 14718167
references.citation: RNA. 2000 Dec;6(12):1773-80
references.pmid: 11142377
references.citation: Genes Dev. 2003 Dec 15;17(24):3075-86
references.pmid: 14701875
references.citation: Cell. 2008 Aug 22;134(4):624-33
references.pmid: 18724935
references.citation: Mol Cell. 2001 Jun;7(6):1191-200
references.pmid: 11430822
references.citation: Nature. 2006 Mar 23;440(7083):561-4
references.pmid: 16554824
references.citation: J Cell Biol. 2007 Nov 5;179(3):437-49
references.pmid: 17984320
references.citation: EMBO J. 2002 Jan 15;21(1-2):165-74
references.pmid: 11782436
references.citation: Cell. 2001 Nov 16;107(4):451-64
references.pmid: 11719186
references.citation: Mol Cell. 2003 Mar;11(3):745-55
references.pmid: 12667456
references.citation: Mol Cell Biol. 1998 Nov;18(11):6826-38
references.pmid: 9774696
references.citation: Mol Cell. 2004 Jul 2;15(1):5-15
references.pmid: 15225544
references.citation: Nature. 2000 Feb 10;403(6770):623-7
references.pmid: 10688190
references.citation: Methods. 1999 Jan;17(1):28-37
references.pmid: 10075880
references.citation: Science. 2002 Mar 22;295(5563):2258-61
references.pmid: 11910109
references.citation: Nature. 2002 Jan 10;415(6868):180-3
references.pmid: 11805837
references.citation: Mol Cell Biol. 2007 Dec;27(24):8600-11
references.pmid: 17923697
references.citation: Nature. 2006 Sep 14;443(7108):234-7
references.pmid: 16971948
references.citation: J Biol Chem. 2007 Jul 6;282(27):19958-68
references.pmid: 17470429
references.citation: Trends Biochem Sci. 1995 Nov;20(11):465-70
references.pmid: 8578590
references.citation: Mol Cell. 1998 Apr;1(5):649-59
references.pmid: 9660949
references.citation: Genes Dev. 2005 Feb 1;19(3):351-61
references.pmid: 15687258
references.citation: Annu Rev Biochem. 2004;73:861-90
references.pmid: 15189161
references.citation: Nat Rev Mol Cell Biol. 2006 Jun;7(6):415-25
references.pmid: 16723977
references.citation: Nucleic Acids Res. 2006 Jan 03;33(22):7138-50
references.pmid: 16391004
references.citation: J Biol Chem. 1994 Apr 1;269(13):9687-92
references.pmid: 8144558
references.citation: EMBO J. 1997 Dec 15;16(24):7500-10
references.pmid: 9405378
references.citation: RNA. 1997 Mar;3(3):234-44
references.pmid: 9056761
references.citation: Science. 2007 Feb 2;315(5812):646-9
references.pmid: 17272721
references.citation: Mol Cell Biol. 1986 Dec;6(12):4419-24
references.pmid: 3025657
references.citation: Cell. 1989 May 19;57(4):573-83
references.pmid: 2655924
references.citation: Mol Cell. 2000 Mar;5(3):457-67
references.pmid: 10882131
references.citation: Mol Cell. 2007 Feb 23;25(4):559-73
references.pmid: 17317628
references.citation: Mol Cell. 2003 Dec;12(6):1439-52
references.pmid: 14690598
references.citation: Trends Cell Biol. 2008 Mar;18(3):105-11
references.pmid: 18262421
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4569-74
references.pmid: 11283351