Nonsense-mediated mRNA decay factors target short poly(A)-tailed mRNAs lacking a premature termination codon

Toni Gouhier1,2,3, Cosmin Saveanu4,5, Gwenael Badis6,7

  • 1Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS UMR8197, INSERM, PSL Research University, Paris, France.

Nature Communications
|April 17, 2026
PubMed

Insights

Nonsense-mediated mRNA decay (NMD) surveillance degrades faulty mRNAs. New findings reveal NMD machinery also targets normal mRNAs with short poly(A) tails, expanding its known functions in RNA degradation.

Area of Science:

  • Molecular Biology
  • RNA Biology
  • Gene Regulation

Background:

  • Nonsense-mediated mRNA decay (NMD) is a crucial eukaryotic surveillance pathway.
  • NMD degrades messenger RNAs (mRNAs) harboring premature termination codons (PTCs).
  • Recognition of NMD targets typically involves Upf1, Upf2, and Upf3 proteins and is influenced by the distance between the stop codon and poly(A)-binding protein (Pab1).

Purpose of the Study:

  • To investigate the full scope of Upf1-associated RNAs.
  • To characterize the features of NMD targets beyond those with PTCs.
  • To redefine the role of the NMD pathway in RNA degradation.

Main Methods:

  • Utilized Nanopore direct RNA sequencing.
  • Analyzed Upf1-associated RNA populations.
  • Characterized poly(A) tail lengths and presence of PTCs in target mRNAs.

Main Results:

  • PTC-containing NMD targets represent only 6% of Upf1-associated RNA and possess long poly(A) tails.
  • The majority of Upf1-associated mRNAs lack PTCs and have short poly(A) tails, correlating with highly expressed genes.
  • Short poly(A) tails are identified as a key feature for a novel class of Upf1 targets.

Conclusions:

  • The NMD pathway's scope extends beyond PTC-containing mRNAs.
  • Short poly(A) tails define a new category of Upf1 targets.
  • The NMD machinery plays a previously unrecognized role in degrading short poly(A)-tailed mRNAs via decapping.

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