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

Joshua T. Mendell, Neda A. Sharifi, Jennifer L. Meyers, Francisco Martinez-Murillo, Harry C. Dietz

Research output: Contribution to journalArticle

535 Citations (Scopus)

Abstract

Premature termination codons induce rapid transcript degradation in eukaryotic cells through nonsense-mediated mRNA decay (NMD). 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 NMD. 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 NMD. 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.

Original languageEnglish (US)
Pages (from-to)1073-1078
Number of pages6
JournalNature Genetics
Volume36
Issue number10
DOIs
StatePublished - Oct 2004

Fingerprint

Nonsense Mediated mRNA Decay
Noise
Nonsense Codon
Introns
Selenocysteine
Endogenous Retroviruses
Amino Acids
Frameshift Mutation
Terminator Codon
5' Untranslated Regions
Alternative Splicing
3' Untranslated Regions
Eukaryotic Cells
Starvation
Eukaryota
Codon
Open Reading Frames
Homeostasis
Nucleotides
RNA

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. / Mendell, Joshua T.; Sharifi, Neda A.; Meyers, Jennifer L.; Martinez-Murillo, Francisco; Dietz, Harry C.

In: Nature Genetics, Vol. 36, No. 10, 10.2004, p. 1073-1078.

Research output: Contribution to journalArticle

Mendell, Joshua T. ; Sharifi, Neda A. ; Meyers, Jennifer L. ; Martinez-Murillo, Francisco ; Dietz, Harry C. / Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. In: Nature Genetics. 2004 ; Vol. 36, No. 10. pp. 1073-1078.
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