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Identification of elements in human long 3' UTRs that inhibit nonsense-mediated decay

Kalodiah G Toma1, Indrani Rebbapragada2, Sébastien Durand3

  • 1Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA.

RNA (New York, N.Y.)
|March 26, 2015
PubMed

Insights

Many long 3' UTR mRNAs evade nonsense-mediated mRNA decay (NMD) through distinct mechanisms. Researchers identified cis elements in TRAM1 mRNA that inhibit NMD, suggesting evolved evasion strategies for gene expression regulation.

Area of Science:

  • Molecular Biology
  • Gene Expression Regulation
  • RNA Biology

Background:

  • The nonsense-mediated mRNA decay (NMD) pathway degrades aberrant and some endogenous mRNAs with premature termination codons (PTCs).
  • NMD targets mRNAs based on translation termination occurring downstream of the poly(A) tail.
  • Many naturally occurring human mRNAs with long 3' UTRs are resistant to NMD, implying evolved evasion mechanisms.

Purpose of the Study:

  • To investigate mechanisms by which human mRNAs with long 3' UTRs evade NMD.
  • To identify cis-acting elements responsible for NMD resistance in specific long 3' UTR mRNAs.

Main Methods:

  • Analysis of human long 3' UTR mRNAs for NMD sensitivity.
  • Dissection of the TRAM1 mRNA 3' UTR to identify NMD-inhibiting elements.
  • Testing the function of identified cis elements using heterologous reporter mRNAs.

Main Results:

  • A significant subset of human long 3' UTR mRNAs are resistant to NMD.
  • A cis element within the first 200 nucleotides of TRAM1 mRNA inhibits NMD when located downstream of the stop codon.
  • This NMD-inhibiting element is sufficient to repress NMD of reporter mRNAs.
  • Other NMD-evading long 3' UTR mRNAs utilize similar cis elements or alternative NMD-independent mechanisms.

Conclusions:

  • Human mRNAs with long 3' UTRs have evolved diverse strategies to evade NMD.
  • NMD evasion can be mediated by specific cis elements in the 5' region of the 3' UTR.
  • Alternative NMD evasion mechanisms exist, independent of proximal cis elements.
Keywords:
NMD inhibitionUPF1long 3′ UTRnonsense-mediated decay

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