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Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise

Nature Genetics volume 36, pages 1073–1078 (2004)Cite this article

An Erratum to this article was published on 01 November 2004

Abstract

Premature termination codons induce rapid transcript degradation in eukaryotic cells through nonsense-mediated mRNA decay (NMD)1,2. This pathway can modulate phenotypes arising from nonsense or frameshift mutations, but little is known about the physiologic role of NMD in higher eukaryotes. To address this issue, we examined expression profiles in mammalian cells depleted of Rent1 (also called hUpf1), a factor essential for NMD3,4. Upregulated transcripts included those with upstream open reading frames in the 5′ untranslated region, alternative splicing that introduces nonsense codons or frameshifts, introns in the 3′ untranslated region or selenocysteine codons. Transcripts derived from ancient transposons and endogenous retroviruses were also upregulated. These RNAs are unified by the presence of a spliced intron at least 50 nucleotides downstream of a termination codon, a context sufficient to initiate NMD5. Consistent with direct regulation by NMD, representative upregulated transcripts decayed more slowly in cells deficient in NMD. In addition, inhibition of NMD induced by amino acid starvation upregulated transcripts that promote amino acid homeostasis. These results document that nonsense surveillance is a crucial post-transcriptional regulatory event that influences the expression of broad classes of physiologic transcripts, has been functionally incorporated into essential homeostatic mechanisms and suppresses expression of evolutionary remnants.

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Figure 1: Prolonged decay rates and increased steady-state abundance of transcripts identified through expression profiling of Rent1-depleted cells.
Figure 2: Amino acid starvation inhibits NMD and upregulates transcripts required for amino acid homeostasis.

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References

  1. Wagner, E. & Lykke-Andersen, J. mRNA surveillance: the perfect persist. J. Cell Sci. 115, 3033–3038 (2002).

    CAS  PubMed  Google Scholar 

  2. Hentze, M.W. & Kulozik, A.E. A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96, 307–310 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Mendell, J.T., ap Rhys, C.M. & Dietz, H.C. Separable roles for rent1/hUpf1 in altered splicing and decay of nonsense transcripts. Science 298, 419–422 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Sun, X., Perlick, H.A., Dietz, H.C. & Maquat, L.E. A mutated human homologue to yeast Upf1 protein has a dominant-negative effect on the decay of nonsense-containing mRNAs in mammalian cells. Proc. Natl. Acad. Sci. USA 95, 10009–10014 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nagy, E. & Maquat, L.E. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem. Sci. 23, 198–199 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Inoue, K. et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat. Genet. 36, 361–369 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Frischmeyer, P.A. & Dietz, H.C. Nonsense-mediated mRNA decay in health and disease. Hum. Mol. Genet. 8, 1893–1900 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. He, F. et al. Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5′ to 3′ mRNA decay pathways in yeast. Mol. Cell 12, 1439–1452 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Lelivelt, M.J. & Culbertson, M.R. Yeast Upf proteins required for RNA surveillance affect global expression of the yeast transcriptome. Mol. Cell. Biol. 19, 6710–6719 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang, J., Sun, X., Qian, Y. & Maquat, L.E. Intron function in the nonsense-mediated decay of beta-globin mRNA: indications that pre-mRNA splicing in the nucleus can influence mRNA translation in the cytoplasm. RNA 4, 801–815 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang, S., Ruiz-Echevarria, M.J., Quan, Y. & Peltz, S.W. Identification and characterization of a sequence motif involved in nonsense-mediated mRNA decay. Mol. Cell. Biol. 15, 2231–2244 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen, B.P., Liang, G., Whelan, J. & Hai, T. ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms. J. Biol. Chem. 269, 15819–15826 (1994).

    CAS  PubMed  Google Scholar 

  13. Aubel, C., Chabanon, H., Carraro, V., Wallace, H.M. & Brachet, P. Expression of spermidine/spermine N1-acetyltransferase in HeLa cells is regulated by amino acid sufficiency. Int. J. Biochem. Cell. Biol. 35, 1388–1398 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Moriarty, P.M., Reddy, C.C. & Maquat, L.E. 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. 18, 2932–2939 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Robertson, H.M. & Martos, R. Molecular evolution of the second ancient human mariner transposon, Hsmar2, illustrates patterns of neutral evolution in the human genome lineage. Gene 205, 219–228 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Goodchild, N.L., Freeman, J.D. & Mager, D.L. Spliced HERV-H endogenous retroviral sequences in human genomic DNA: evidence for amplification via retrotransposition. Virology 206, 164–173 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Lindeskog, M. & Blomberg, J. Spliced human endogenous retroviral HERV-H env transcripts in T-cell leukaemia cell lines and normal leukocytes: alternative splicing pattern of HERV-H transcripts. J. Gen. Virol. 78, 2575–2585 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Lewis, B.P., Green, R.E. & Brenner, S.E. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc. Natl. Acad. Sci. USA 100, 189–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Pan, Y., Chen, H., Siu, F. & Kilberg, M.S. Amino acid deprivation and endoplasmic reticulum stress induce expression of multiple activating transcription factor-3 mRNA species that, when overexpressed in HepG2 cells, modulate transcription by the human asparagine synthetase promoter. J. Biol. Chem. 278, 38402–38412 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Siu, F., Bain, P.J., LeBlanc-Chaffin, R., Chen, H. & Kilberg, M.S. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. J. Biol. Chem. 277, 24120–24127 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Pain, V.M. Translational control during amino acid starvation. Biochimie 76, 718–728 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Averous, J. et al. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. J. Biol. Chem. 279, 5288–5297 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Forsberg, H. & Ljungdahl, P.O. Sensors of extracellular nutrients in Saccharomyces cerevisiae. Curr. Genet. 40, 91–109 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Schreve, J.L. & Garrett, J.M. Yeast Agp2p and Agp3p function as amino acid permeases in poor nutrient conditions. Biochem. Biophys. Res. Commun. 313, 745–751 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Hardwick, J.S., Kuruvilla, F.G., Tong, J.K., Shamji, A.F. & Schreiber, S.L. Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc. Natl. Acad. Sci. USA 96, 14866–14870 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Natarajan, K. et al. Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast. Mol. Cell. Biol. 21, 4347–4368 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gatfield, D., Unterholzner, L., Ciccarelli, F.D., Bork, P. & Izaurralde, E. Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways. EMBO J. 22, 3960–3970 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Medghalchi, S.M. et al. Rent1, a trans-effector of nonsense-mediated mRNA decay, is essential for mammalian embryonic viability. Hum. Mol. Genet. 10, 99–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Leeds, P., Peltz, S.W., Jacobson, A. & Culbertson, M.R. The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon. Genes Dev. 5, 2303–2314 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Leeds, P., Wood, J.M., Lee, B.S. & Culbertson, M.R. Gene products that promote mRNA turnover in Saccharomyces cerevisiae. Mol. Cell. Biol. 12, 2165–2177 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank D. Arking for assistance with statistical analyses; M. Awad and C. ap Rhys for discussions; and M. Wilkinson, J. Lykke-Andersen, J. Steitz and K. O'Donnell for reagents. Microarray hybridizations and data analysis were done at the Johns Hopkins Medical Institutions Microarray Core Facility. H.C.D. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 539 Broadway Research Building, 733 N. Broadway, Baltimore, 21205, Maryland, USA

    Joshua T Mendell, Neda A Sharifi & Harry C Dietz

  2. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 539 Broadway Research Building, 733 N. Broadway, Baltimore, 21205, Maryland, USA

    Jennifer L Meyers & Harry C Dietz

  3. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 808 PCTB, 725 North Wolfe Street, Baltimore, 21205, Maryland, USA

    Francisco Martinez-Murillo

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  1. Joshua T Mendell
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Correspondence to Harry C Dietz.

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Supplementary information

Supplementary Table 1

Putative NMD-inducing features of transcripts upregulated in rent1/hUpf1-depleted cells. (XLS 57 kb)

Supplementary Table 2

Transcripts downregulated in rent1/hUpf1-depleted cells. (XLS 37 kb)

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Mendell, J., Sharifi, N., Meyers, J. et al. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet 36, 1073–1078 (2004). https://doi.org/10.1038/ng1429

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