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A cell type–restricted mRNA surveillance pathway triggered by ribosome extension into the 3′ untranslated region

Nature Structural & Molecular Biology volume 14, pages 670–676 (2007)Cite this article

Abstract

The accuracy of eukaryotic gene expression is monitored at multiple levels. Surveillance pathways have been identified that degrade messenger RNAs containing nonsense mutations, harboring stalled ribosomes or lacking termination codons. Here we report a previously uncharacterized surveillance pathway triggered by ribosome extension into the 3′ untranslated region. This ribosome extension–mediated decay, REMD, accounts for marked repression of protein synthesis from a human α-globin gene containing a prevalent antitermination mutation. REMD can be mechanistically distinguished from other surveillance pathways by its functional linkage to accelerated deadenylation, by its independence from the NMD factor Upf1 and by cell-type restriction. This unusual pathway of mRNA surveillance is likely to act as a modifier of additional genetic defects and may reflect post-transcriptional controls particular to erythroid and other differentiated cell lineages.

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Figure 1: The human α-globin mRNA is markedly destabilized by the Constant Spring mutation.
Figure 2: Extension of the ribosome into the 3′ UTR triggers two independent destabilization events linked to accelerated deadenylation.
Figure 3: Destabilization of the antiterminated α-globin mRNA is uniquely dependent on 3′ deadenylation and is independent of Upf1.
Figure 4: REMD is restricted by cell type.

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Acknowledgements

We thank A.-B. Shyu of The University of Texas Medical School at Houston for the kind gift of plasmids encoding the dominant-negative mutants of deadenylases Ccr4, Pan2 and Parn, and N. Cooke of The University of Pennsylvania for her critical comments. This work was supported by US National Institutes of Health grants R37-HL65449 and PO1 CA72765 (S.A.L.).

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  1. Department of Genetics and Department of Medicine, University of Pennsylvania School of Medicine, 415 Curie Blvd., CRB 430, Philadelphia, 19104, Pennsylvania, USA

    Jian Kong & Stephen A Liebhaber

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Correspondence to Stephen A Liebhaber.

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Supplementary information

Supplementary Fig. 1

Extension of the antiterminated ribosome into the 3′ untranslated region triggers two independent destabilization events, an α-complex–dependent action and an α-complex–independent ribosome-extension effect. (PDF 267 kb)

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Kong, J., Liebhaber, S. A cell type–restricted mRNA surveillance pathway triggered by ribosome extension into the 3′ untranslated region. Nat Struct Mol Biol 14, 670–676 (2007). https://doi.org/10.1038/nsmb1256

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