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Failsafe nonsense-mediated mRNA decay does not detectably target eIF4E-bound mRNA

Nature Structural & Molecular Biology volume 14, pages 974–979 (2007)Cite this article

Abstract

Nonsense-mediated mRNA decay (NMD) generally eliminates messenger RNAs that prematurely terminate translation and occurs in all eukaryotes that have been studied, although with mechanistic variations. In mammals, NMD seems to be restricted to newly synthesized mRNA that is bound by the cap-binding heterodimer CBP80-CBP20 (CBP80/20) and typically has at least one exon junction complex (EJC) situated downstream of the nonsense codon and added post-splicing. However, mammalian NMD can also target spliced mRNA lacking an EJC downstream of the nonsense codon. Here we provide evidence that this additional pathway, known as failsafe NMD, likewise seems to be restricted to CBP80/20-bound mRNA and does not detectably target its subsequently remodeled product, eIF4E-bound mRNA. Our studies, including analyses of factor dependence, reveal important shared features of the two mammalian-cell NMD pathways as well as fundamental differences between NMD in mammals and Saccharomyces cerevisiae.

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Figure 1: Failsafe Gl NMD targets nucleus-associated transcripts.
Figure 2: 4E-BP1 does not inhibit failsafe Gl NMD.
Figure 3: Failsafe Gl NMD reduces the abundance of CBP80-bound mRNA and its eIF4E-bound product to the same percentage of the amount of nonsense-free mRNA.
Figure 4: Effects of downregulating Upf2, Y14 or eIF4AIII on classical or failsafe Gl or TPI NMD.

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Acknowledgements

We thank F. Lejeune and X. Li for contributions to early phases of this work, O. Isken for comments on the manuscript, E. Izaurralde (Max Planck Institute-Tübingen) for anti-CBP80, H. Baumann and B. Held (Roswell Park Cancer Institute) for anti-MUP, G. Dreyfuss (University of Pennsylvania) for anti-Y14, A. Mayeda (Fujita Health University) for anti-RNPS1, N. Sonenberg (McGill University) for anti-eIF3b, anti-eIF4AIII, anti-4E-BP1 and the pACTAG2 plasmids, and D. Scofield for helpful conversations. This work was supported by US National Institutes of Health grant GM074593 to L.E.M. N.H. was partially supported by a Fellowship from the Japan Society for the Promotion of Science.

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Author notes

  1. Nao Hosoda & Yoon Ki Kim

    Present address: Present addresses: Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan (N.H.), and School of Life Sciences and Biotechnology, Korea University, Anam-Dong, Seongbuk-Gu, Seoul 136-701, Republic of Korea (Y.K.K.).,

  2. Daiki Matsuda and Nao Hosoda: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Box 712, Rochester, 14642, New York, USA

    Daiki Matsuda, Nao Hosoda, Yoon Ki Kim & Lynne E Maquat

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Contributions

D.M., N.H. and Y.K.K. and L.E.M. designed experiments and analyzed data; D.M., N.H. and Y.K.K. performed experiments; and D.M. and L.E.M. wrote the paper.

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Correspondence to Lynne E Maquat.

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Matsuda, D., Hosoda, N., Kim, Y. et al. Failsafe nonsense-mediated mRNA decay does not detectably target eIF4E-bound mRNA. Nat Struct Mol Biol 14, 974–979 (2007). https://doi.org/10.1038/nsmb1297

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