lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements (original) (raw)

Nature volume 470, pages 284–288 (2011)Cite this article

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Abstract

Staufen 1 (STAU1)-mediated messenger RNA decay (SMD) involves the degradation of translationally active mRNAs whose 3′-untranslated regions (3′ UTRs) bind to STAU1, a protein that binds to double-stranded RNA1,2. Earlier studies defined the STAU1-binding site within ADP-ribosylation factor 1 (ARF1) mRNA as a 19-base-pair stem with a 100-nucleotide apex2. However, we were unable to identify comparable structures in the 3′ UTRs of other targets of SMD. Here we show that STAU1-binding sites can be formed by imperfect base-pairing between an Alu element in the 3′ UTR of an SMD target and another Alu element in a cytoplasmic, polyadenylated long non-coding RNA (lncRNA). An individual lncRNA can downregulate a subset of SMD targets, and distinct lncRNAs can downregulate the same SMD target. These are previously unappreciated functions of non-coding RNAs and Alu elements3,4,5. Not all mRNAs that contain an Alu element in the 3′ UTR are targeted for SMD even in the presence of a complementary lncRNA that targets other mRNAs for SMD. Most known _trans_-acting RNA effectors consist of fewer than 200 nucleotides, and these include small nucleolar RNAs and microRNAs. Our finding that the binding of STAU1 to mRNAs can be transactivated by lncRNAs uncovers an unexpected strategy that cells use to recruit proteins to mRNAs and mediate the decay of these mRNAs. We name these lncRNAs half-STAU1-binding site RNAs (1/2-sbsRNAs).

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Acknowledgements

We thank D. Mathews and A. Grossfield for the use of computer clusters, D. Matthews for access to the program Structure 5.0, K. Nerhrke for fluorescence microscope time, S. de Lucas and J. Ortíz for anti-STAU1 antibodies, M. Gorospe for pcDNA3-MS2bsX12, S. Higgins and P. Higgins for HaCaT cells and advice on the scrape-injury repair assay, J. Wang for the initial BAG5 mRNA assays, and O. Isken, M. Gleghorn and D. Matthews for comments on the manuscript. This work was supported by the National Institutes of Health (GM074593 to L.E.M.) and an Elon Huntington Hooker Graduate Student Fellowship (C.G.).

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, 14642, New York, USA
    Chenguang Gong & Lynne E. Maquat
  2. Center for RNA Biology, University of Rochester, Rochester, 14642, New York, USA
    Chenguang Gong & Lynne E. Maquat

Authors

  1. Chenguang Gong
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  2. Lynne E. Maquat
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Contributions

C.G. wrote the Perl programs and performed the bioinformatics analyses and wet-bench experiments. C.G. and L.E.M. analysed the computational data, designed the wet-bench experiments, analysed the resultant data and wrote the manuscript.

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Correspondence toLynne E. Maquat.

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Gong, C., Maquat, L. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements.Nature 470, 284–288 (2011). https://doi.org/10.1038/nature09701

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Editorial Summary

Role for long non-coding RNAs

The RNA-binding protein Staufen1 (STAU1) promotes the degradation of double-stranded messenger RNA in the process known as Staufen-mediated decay (SMD). STAU1 binds to transcripts in the 3′ untranslated region (UTR), and although a specific stem-loop binding site had been defined for one SMD target, it was unclear how STAU1 was directed to other SMD targets that lack this structure. Chenguang Gong and Lynne Maquat report that pairing of Alu element sequences in long non-coding RNAs (lncRNAs) and in the 3′ UTR of the SMD target generates a double-stranded RNA structure that STAU1 recognizes. This result highlights a new function for lncRNAs.