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An alternative branch of the nonsense‐mediated decay pathway

Wai‐Kin Chan, Lulu Huang, Jayanthi P Gudikote, Yao‐Fu Chang, J Saadi Imam, James A MacLean, Miles F Wilkinson

Author Affiliations

  1. Wai‐Kin Chan1,
  2. Lulu Huang1,
  3. Jayanthi P Gudikote1,
  4. Yao‐Fu Chang1,
  5. J Saadi Imam1,
  6. James A MacLean II1 and
  7. Miles F Wilkinson*,1
  1. 1 Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  1. *Corresponding author. Department of Biochemistry and Molecular Biology, Unit 1000, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Tel.: +1 713 563 3215; Fax: +1 713 563 3375; E-mail: mwilkins{at}mdanderson.org
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Abstract

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 TCRβ 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 TCRβ NMD. Mapping experiments revealed the identity of TCRβ sequences that elicit a switch to UPF3b dependence. This regulation is not a peculiarity of TCRβ, 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.

  • Received November 1, 2006.
  • Accepted February 5, 2007.
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