An alternative branch of the nonsense-mediated decay pathway

EMBO J. 2007 Apr 4;26(7):1820-30. doi: 10.1038/sj.emboj.7601628. Epub 2007 Mar 15.


The T-cell receptor (TCR) locus undergoes programmed rearrangements that frequently generate premature termination codons (PTCs). The PTC-bearing transcripts derived from such nonproductively rearranged genes are dramatically downregulated by the nonsense-mediated decay (NMD) pathway. Here, we show that depletion of the NMD factor UPF3b does not impair TCRbeta NMD, thereby distinguishing it from classical NMD. Depletion of the related factor UPF3a, by itself or in combination with UPF3b, also has no effect on TCRbeta NMD. Mapping experiments revealed the identity of TCRbeta sequences that elicit a switch to UPF3b dependence. This regulation is not a peculiarity of TCRbeta, as we identified many wild-type genes, including one essential for NMD, that transcribe NMD-targeted mRNAs whose downregulation is little or not affected by UPF3a and UPF3b depletion. We propose that we have uncovered an alternative branch of the NMD pathway that not only degrades aberrant mRNAs but also regulates normal mRNAs, including one that participates in a negative feedback loop controlling the magnitude of NMD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Clone Cells
  • Codon, Nonsense / genetics*
  • Codon, Nonsense / metabolism*
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Introns / genetics
  • Mice
  • RNA Helicases
  • RNA Stability*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Sequence Deletion
  • Trans-Activators / metabolism
  • VDJ Exons / genetics


  • Codon, Nonsense
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Receptors, Antigen, T-Cell, alpha-beta
  • Trans-Activators
  • UPF3A protein, human
  • UPF3B protein, human
  • RNA Helicases
  • UPF1 protein, human