title: An alternative branch of the nonsense-mediated decay pathway.
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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Wai-Kin
authors.initials: WK
authors.lastname: Chan
authors.forename: Lulu
authors.initials: L
authors.lastname: Huang
authors.forename: Jayanthi P
authors.initials: JP
authors.lastname: Gudikote
authors.forename: Yao-Fu
authors.initials: YF
authors.lastname: Chang
authors.forename: J Saadi
authors.initials: JS
authors.lastname: Imam
authors.forename: James A
authors.initials: JA
authors.lastname: MacLean
authors.forename: Miles F
authors.initials: MF
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D002999:Clone Cells; D018389:Codon, Nonsense / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D020365:RNA Helicases; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015534:Trans-Activators / Q000378:metabolism; D050441:VDJ Exons / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015534:Trans-Activators; C435487:UPF3A protein, human; C435488:UPF3B protein, human; D020365:RNA Helicases; C101828:UPF1 protein, human