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      lncRNAs transactivate Staufen1-mediated mRNA decay by duplexing with 3'UTRs via Alu elements

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          Abstract

          Staufen1 (STAU1)-mediated mRNA decay (SMD) degrades translationally active mRNAs that bind the double-stranded (ds)RNA binding protein STAU1 within their 3'-untranslated regions (3'UTRs) 1, 2. Earlier studies defined the STAU1 binding site (SBS) within ADP ribosylation factor 1 (ARF1) mRNA as a 19-base-pair stem with a 100-nucleotide apex 2. However, we were unable to identify comparable structures within the 3'UTRs of other SMD targets. Here we report that SBSs can be formed by imperfect base-pairing between an Alu element within the 3'UTR of an SMD target and another Alu element within a cytoplasmic and polyadenylated long noncoding RNA (lncRNA). Individual lncRNAs can downregulate a subset of SMD targets, and distinct lncRNAs can downregulate the same SMD target. These are previously unappreciated functions for ncRNAs and Alu elements 35. Not all mRNAs that contain a 3'UTR Alu element are targeted for SMD despite 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 include snoRNAs and microRNAs. Our finding that STAU1 binding to mRNAs can be transactivated by lncRNAs uncovers an unexpected strategy used by cells to recruit proteins to mRNAs and mediate their decay. We name these lncRNAs “half(½)-sbsRNAs”.

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          Most cited references13

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          Thermodynamic parameters for an expanded nearest-neighbor model for formation of RNA duplexes with Watson-Crick base pairs.

          Improved thermodynamic parameters for prediction of RNA duplex formation are derived from optical melting studies of 90 oligoribonucleotide duplexes containing only Watson-Crick base pairs. To test end or base composition effects, new sets of duplexes are included that have identical nearest neighbors, but different base compositions and therefore different ends. Duplexes with terminal GC pairs are more stable than duplexes with the same nearest neighbors but terminal AU pairs. Penalizing terminal AU base pairs by 0.45 kcal/mol relative to terminal GC base pairs significantly improves predictions of DeltaG degrees37 from a nearest-neighbor model. A physical model is suggested in which the differential treatment of AU and GC ends accounts for the dependence of the total number of Watson-Crick hydrogen bonds on the base composition of a duplex. On average, the new parameters predict DeltaG degrees37, DeltaH degrees, DeltaS degrees, and TM within 3.2%, 6.0%, 6.8%, and 1.3 degreesC, respectively. These predictions are within the limit of the model, based on experimental results for duplexes predicted to have identical thermodynamic parameters.
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            Genome-wide transcription and the implications for genomic organization.

            Recent evidence of genome-wide transcription in several species indicates that the amount of transcription that occurs cannot be entirely accounted for by current sets of genome-wide annotations. Evidence indicates that most of both strands of the human genome might be transcribed, implying extensive overlap of transcriptional units and regulatory elements. These observations suggest that genomic architecture is not colinear, but is instead interleaved and modular, and that the same genomic sequences are multifunctional: that is, used for multiple independently regulated transcripts and as regulatory regions. What are the implications and consequences of such an interleaved genomic architecture in terms of increased information content, transcriptional complexity, evolution and disease states?
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              Mammalian Staufen1 recruits Upf1 to specific mRNA 3'UTRs so as to elicit mRNA decay.

              Mammalian Staufen (Stau)1 is an RNA binding protein that is thought to function in mRNA transport and translational control. Nonsense-mediated mRNA decay (NMD) degrades abnormal and natural mRNAs that terminate translation sufficiently upstream of a splicing-generated exon-exon junction. Here we describe an mRNA decay mechanism that involves Stau1, the NMD factor Upf1, and a termination codon. Unlike NMD, this mechanism does not involve pre-mRNA splicing and occurs when Upf2 or Upf3X is downregulated. Stau1 binds directly to Upf1 and elicits mRNA decay when tethered downstream of a termination codon. Stau1 also interacts with the 3'-untranslated region of ADP-ribosylation factor (Arf)1 mRNA. Accordingly, downregulating either Stau1 or Upf1 increases Arf1 mRNA stability. These findings suggest that Arf1 mRNA is a natural target for Stau1-mediated decay, and data indicate that other mRNAs are also natural targets. We discuss this pathway as a means for cells to downregulate the expression of Stau1 binding transcripts.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                29 November 2010
                10 February 2011
                10 August 2011
                : 470
                : 7333
                : 284-288
                Affiliations
                [1 ]Department of Biochemistry and Biophysics and Center for RNA Biology, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA
                Author notes

                Author Contributions C.G. wrote the Perl programs and performed the bioinformatics analyses and wet-bench experiments. C.G. and L.E.M. analyzed the forthcoming computational data, designed the wet-bench experiments, analyzed the resulting data, and wrote the manuscript.

                Correspondence to L.E.M. ( lynne_maquat@ 123456urmc.rochester.edu ).
                Article
                nihpa254762
                10.1038/nature09701
                3073508
                21307942
                2cd09fd0-1b0b-4a4b-b4ab-b625f918caaa

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM074593-27 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM074593-26 ||GM
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