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RNA splicing promotes translation and RNA surveillance

Nature Structural & Molecular Biology volume 12, pages 801809 (2005) | Download Citation

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Abstract

Aberrant mRNAs harboring premature termination codons (PTCs or nonsense codons) are degraded by the nonsense-mediated mRNA decay (NMD) pathway. mRNAs transcribed from genes that naturally acquire PTCs during lymphocyte development are strongly downregulated by PTCs. Here we show that a signal essential for this robust mRNA downregulatory response is efficient RNA splicing. Strong mRNA downregulation can be conferred on a poor NMD substrate by either strengthening its splicing signals or removing its weak introns. Efficient splicing also strongly promotes translation, providing a molecular explanation for enhanced NMD and suggesting that efficient splicing may have evolved to enhance both protein production and RNA surveillance. Our results suggest simple approaches for increasing protein expression from expression vectors and treating human genetic diseases caused by nonsense and frameshift mutations.

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Acknowledgements

We thank Y.-J. Liu and Y.-H. Wang for technical advice on FACS analysis, A. Bhalla for technical assistance and G. Cote for useful comments. This study was supported by the US National Institutes of Health grant GM058595 and the Kleberg Fund for Innovative Research Program Allocation for IRG (M.D. Anderson Cancer Center).

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Affiliations

  1. Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

    • Jayanthi P Gudikote
    • , J Saadi Imam
    • , Ramon F Garcia
    •  & Miles F Wilkinson

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Miles F Wilkinson.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Deletions in the VDJ exon do not affect NMD.

  2. 2.

    Supplementary Fig. 2

    A mutation in the 3′ splice site of TCRβ IVS1 dramatically reduces the magnitude of downregulation in response to a PTC.

  3. 3.

    Supplementary Methods

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DOI

https://doi.org/10.1038/nsmb980

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