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PMID: 22028362 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Autoregulation of the nonsense-mediated mRNA decay pathway in human cells.

RNA (New York, N.Y.) ·Vol. 17 ·No. 12 ·2011-12-00 ·Pages 2108-18

Yepiskoposyan H, Aeschimann F, Nilsson D, Okoniewski M, Mühlemann O

Abstract

Nonsense-mediated mRNA decay (NMD) is traditionally portrayed as a quality-control mechanism that degrades mRNAs with truncated open reading frames (ORFs). However, it is meanwhile clear that NMD also contributes to the post-transcriptional gene regulation of numerous physiological mRNAs. To identify endogenous NMD substrate mRNAs and analyze the features that render them sensitive to NMD, we performed transcriptome profiling of human cells depleted of the NMD factors UPF1, SMG6, or SMG7. It revealed that mRNAs up-regulated by NMD abrogation had a greater median 3'-UTR length compared with that of the human mRNAome and were also enriched for 3'-UTR introns and uORFs. Intriguingly, most mRNAs coding for NMD factors were among the NMD-sensitive transcripts, implying that the NMD process is autoregulated. These mRNAs all possess long 3' UTRs, and some of them harbor uORFs. Using reporter gene assays, we demonstrated that the long 3' UTRs of UPF1, SMG5, and SMG7 mRNAs are the main NMD-inducing features of these mRNAs, suggesting that long 3' UTRs might be a frequent trigger of NMD.

MeSH Terms
3' Untranslated Regions Gene Expression Profiling Gene Expression Regulation HeLa Cells Homeostasis/genetics Humans Introns Nonsense Mediated mRNA Decay Open Reading Frames RNA, Messenger/metabolism
Chemicals
3' Untranslated Regions RNA, Messenger
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yepiskoposyan Hasmik
Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.
Aeschimann Florian
Nilsson Daniel
Okoniewski Michal
Mühlemann Oliver
References (58)
58 references, click to expand
  1. A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay.
    PLoS Biol. 2008 Apr 29;6(4):e111 PMID: 18447585
  2. Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response.
    Mol Cell Biol. 2008 Jun;28(11):3729-41 PMID: 18362164
  3. Recognition of nonsense mRNA: towards a unified model.
    Biochem Soc Trans. 2008 Jun;36(Pt 3):497-501 PMID: 18481988
  4. The abundance of RNPS1, a protein component of the exon junction complex, can determine the variability in efficiency of the Nonsense Mediated Decay pathway.
    Nucleic Acids Res. 2007;35(13):4542-51 PMID: 17586820
  5. Identification of a microRNA that activates gene expression by repressing nonsense-mediated RNA decay.
    Mol Cell. 2011 May 20;42(4):500-10 PMID: 21596314
  6. Plant upstream ORFs can trigger nonsense-mediated mRNA decay in a size-dependent manner.
    Plant Mol Biol. 2009 Nov;71(4-5):367-78 PMID: 19653106
  7. SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan.
    RNA. 2008 Dec;14(12):2609-17 PMID: 18974281
  8. Regulation of multiple core spliceosomal proteins by alternative splicing-coupled nonsense-mediated mRNA decay.
    Mol Cell Biol. 2008 Jul;28(13):4320-30 PMID: 18443041
  9. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance.
    Trends Biochem Sci. 1998 Jun;23(6):198-9 PMID: 9644970
  10. A programmed -1 ribosomal frameshift signal can function as a cis-acting mRNA destabilizing element.
    Nucleic Acids Res. 2004 Feb 03;32(2):784-90 PMID: 14762205
  11. An alternative branch of the nonsense-mediated decay pathway.
    EMBO J. 2007 Apr 4;26(7):1820-30 PMID: 17363904
  12. A GFP-based reporter system to monitor nonsense-mediated mRNA decay.
    Nucleic Acids Res. 2005 Mar 30;33(6):e54 PMID: 15800205
  13. Unstable beta-globin mRNA in mRNA-deficient beta o thalassemia.
    Cell. 1981 Dec;27(3 Pt 2):543-53 PMID: 6101206
  14. Upf1, an RNA helicase required for nonsense-mediated mRNA decay, modulates the transcriptional response to oxidative stress in fission yeast.
    Mol Cell Biol. 2006 Sep;26(17):6347-56 PMID: 16914721
  15. Long 3'-UTRs target wild-type mRNAs for nonsense-mediated mRNA decay in Saccharomyces cerevisiae.
    Nucleic Acids Res. 2009 May;37(9):2771-8 PMID: 19270062
  16. Gene set coregulated by the Saccharomyces cerevisiae nonsense-mediated mRNA decay pathway.
    Eukaryot Cell. 2005 Dec;4(12):2066-77 PMID: 16339724
  17. NMD is essential for hematopoietic stem and progenitor cells and for eliminating by-products of programmed DNA rearrangements.
    Genes Dev. 2008 May 15;22(10):1381-96 PMID: 18483223
  18. SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells.
    Nat Struct Mol Biol. 2009 Jan;16(1):49-55 PMID: 19060897
  19. Nonsense mutations in the human beta-globin gene lead to unexpected levels of cytoplasmic mRNA accumulation.
    Blood. 2000 Oct 15;96(8):2895-901 PMID: 11023527
  20. The eukaryotic polypeptide chain releasing factor (eRF3/GSPT) carrying the translation termination signal to the 3'-Poly(A) tail of mRNA. Direct association of erf3/GSPT with polyadenylate-binding protein.
    J Biol Chem. 1999 Jun 11;274(24):16677-80 PMID: 10358005
  21. Selenium deficiency reduces the abundance of mRNA for Se-dependent glutathione peroxidase 1 by a UGA-dependent mechanism likely to be nonsense codon-mediated decay of cytoplasmic mRNA.
    Mol Cell Biol. 1998 May;18(5):2932-9 PMID: 9566912
  22. Characterization of the biochemical properties of the human Upf1 gene product that is involved in nonsense-mediated mRNA decay.
    RNA. 2000 Sep;6(9):1226-35 PMID: 10999600
  23. Nonsense-mediated mRNA decay factors act in concert to regulate common mRNA targets.
    RNA. 2005 Oct;11(10):1530-44 PMID: 16199763
  24. Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay.
    Genes Dev. 2001 Sep 1;15(17):2215-28 PMID: 11544179
  25. The meaning of nonsense.
    Trends Cell Biol. 2008 Jul;18(7):315-21 PMID: 18524595
  26. Purification and characterization of the Upf1 protein: a factor involved in translation and mRNA degradation.
    RNA. 1995 Aug;1(6):610-23 PMID: 7489520
  27. Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay.
    Genes Dev. 2006 Feb 1;20(3):355-67 PMID: 16452507
  28. The relationship between the evolution of microRNA targets and the length of their UTRs.
    BMC Genomics. 2009 Sep 14;10:431 PMID: 19751524
  29. Genome-wide identification of alternative splice forms down-regulated by nonsense-mediated mRNA decay in Drosophila.
    PLoS Genet. 2009 Jun;5(6):e1000525 PMID: 19543372
  30. The upstream open reading frame of the Arabidopsis AtMHX gene has a strong impact on transcript accumulation through the nonsense-mediated mRNA decay pathway.
    Plant J. 2009 Dec;60(6):1031-42 PMID: 19754518
  31. Regulated degradation of replication-dependent histone mRNAs requires both ATR and Upf1.
    Nat Struct Mol Biol. 2005 Sep;12(9):794-800 PMID: 16086026
  32. Upf1 senses 3'UTR length to potentiate mRNA decay.
    Cell. 2010 Oct 29;143(3):379-89 PMID: 21029861
  33. Inter-kingdom conservation of mechanism of nonsense-mediated mRNA decay.
    EMBO J. 2008 Jun 4;27(11):1585-95 PMID: 18451801
  34. A 3' UTR sequence stabilizes termination codons in the unspliced RNA of Rous sarcoma virus.
    RNA. 2006 Jan;12(1):102-10 PMID: 16301601
  35. Ensembl 2011.
    Nucleic Acids Res. 2011 Jan;39(Database issue):D800-6 PMID: 21045057
  36. Posttranscriptional gene regulation by spatial rearrangement of the 3' untranslated region.
    PLoS Biol. 2008 Apr 29;6(4):e92 PMID: 18447580
  37. A conserved role for cytoplasmic poly(A)-binding protein 1 (PABPC1) in nonsense-mediated mRNA decay.
    EMBO J. 2007 Mar 21;26(6):1591-601 PMID: 17318186
  38. Early nonsense: mRNA decay solves a translational problem.
    Nat Rev Mol Cell Biol. 2006 Jun;7(6):415-25 PMID: 16723977
  39. The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay.
    EMBO J. 2001 Sep 3;20(17):4987-97 PMID: 11532962
  40. Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors.
    Cell Mol Life Sci. 2010 Mar;67(5):677-700 PMID: 19859661
  41. Efficient downregulation of immunoglobulin mu mRNA with premature translation-termination codons requires the 5'-half of the VDJ exon.
    Nucleic Acids Res. 2004 Jun 21;32(11):3304-15 PMID: 15210863
  42. Interference of nonsense mutations with eukaryotic messenger RNA stability.
    Proc Natl Acad Sci U S A. 1979 Oct;76(10):5134-7 PMID: 388431
  43. A faux 3'-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay.
    Nature. 2004 Nov 4;432(7013):112-8 PMID: 15525991
  44. Processing bodies are not required for mammalian nonsense-mediated mRNA decay.
    RNA. 2009 Jul;15(7):1265-73 PMID: 19474145
  45. Both introns and long 3'-UTRs operate as cis-acting elements to trigger nonsense-mediated decay in plants.
    Nucleic Acids Res. 2006;34(21):6147-57 PMID: 17088291
  46. Nonsense-mediated mRNA decay: Target genes and functional diversification of effectors.
    Trends Biochem Sci. 2006 Nov;31(11):639-46 PMID: 17010613
  47. Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway.
    Genes Dev. 2007 May 1;21(9):1075-85 PMID: 17437990
  48. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans.
    Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):189-92 PMID: 12502788
  49. Yeast Upf proteins required for RNA surveillance affect global expression of the yeast transcriptome.
    Mol Cell Biol. 1999 Oct;19(10):6710-9 PMID: 10490610
  50. An internal open reading frame triggers nonsense-mediated decay of the yeast SPT10 mRNA.
    EMBO J. 1999 Nov 1;18(21):6134-45 PMID: 10545123
  51. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise.
    Nat Genet. 2004 Oct;36(10):1073-8 PMID: 15448691
  52. Aberrant mRNAs with extended 3' UTRs are substrates for rapid degradation by mRNA surveillance.
    RNA. 1999 Oct;5(10):1299-307 PMID: 10573121
  53. hUPF2 silencing identifies physiologic substrates of mammalian nonsense-mediated mRNA decay.
    Mol Cell Biol. 2006 Feb;26(4):1272-87 PMID: 16449641
  54. SMG7 acts as a molecular link between mRNA surveillance and mRNA decay.
    Mol Cell. 2004 Nov 19;16(4):587-96 PMID: 15546618
  55. This message was inspected by Upf1: 3'UTR length sensing in mRNA quality control.
    Cell Cycle. 2011 Feb 1;10(3):372-3 PMID: 21248469
  56. Linear models and empirical bayes methods for assessing differential expression in microarray experiments.
    Stat Appl Genet Mol Biol. 2004;3:Article3 PMID: 16646809
  57. RNA homeostasis governed by cell type-specific and branched feedback loops acting on NMD.
    Mol Cell. 2011 Sep 16;43(6):950-61 PMID: 21925383
  58. Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5' to 3' mRNA decay pathways in yeast.
    Mol Cell. 2003 Dec;12(6):1439-52 PMID: 14690598
Article Info
Journal
RNA (New York, N.Y.)
Abbr.
RNA
ISSN
1469-9001
DOI
10.1261/rna.030247.111
Published
2011-12-00
Epub
2011-00-25
Pages
2108-18
Language
English
Region
United States
NLM ID
9509184
PMCID
PMC3222124
Subset
IM
Grants
European Research Council · 207419 · International
External Links
PubMed source DOI: 10.1261/rna.030247.111 PMC Full Text View journal details
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