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The RNA-binding Protein KSRP Promotes the Biogenesis of a Subset of miRNAs

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      Abstract

      Consistent with the role of microRNAs (miRNAs) in down-regulating gene expression by reducing translation and/or stability of target mRNAs 1, the levels of specific miRNAs are important for correct embryonic development and have been linked to several forms of cancer 2- 4. However, the regulatory mechanisms by which primary miRNAs (pri-miRNAs) are processed first to precursor miRNAs (pre-miRNAs) and then to mature miRNAs by the multiprotein Drosha and Dicer complexes 5- 8, respectively, remain largely unknown. The KH-type splicing regulatory protein (KSRP) interacts with single strand AU-rich elements (ARE)-containing mRNAs and is a key mediator of mRNA decay 9, 10. Here, we show that KSRP also serves as a component of both Drosha and Dicer complexes and regulates the biogenesis of a subset of miRNAs. KSRP binds with high affinity to the terminal loop (TL) of the target miRNA precursors and promotes their maturation. This mechanism is required for specific changes in target mRNA expression that affects specific biological programs, including proliferation, apoptosis and differentiation. These findings reveal an unexpected mechanism that links KSRP to the machinery regulating maturation of a cohort of miRNAs, that, in addition to its role in promoting mRNA decay, independently serves to integrate specific regulatory programs of protein expression.

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      Most cited references 49

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      NMRPipe: a multidimensional spectral processing system based on UNIX pipes.

      The NMRPipe system is a UNIX software environment of processing, graphics, and analysis tools designed to meet current routine and research-oriented multidimensional processing requirements, and to anticipate and accommodate future demands and developments. The system is based on UNIX pipes, which allow programs running simultaneously to exchange streams of data under user control. In an NMRPipe processing scheme, a stream of spectral data flows through a pipeline of processing programs, each of which performs one component of the overall scheme, such as Fourier transformation or linear prediction. Complete multidimensional processing schemes are constructed as simple UNIX shell scripts. The processing modules themselves maintain and exploit accurate records of data sizes, detection modes, and calibration information in all dimensions, so that schemes can be constructed without the need to explicitly define or anticipate data sizes or storage details of real and imaginary channels during processing. The asynchronous pipeline scheme provides other substantial advantages, including high flexibility, favorable processing speeds, choice of both all-in-memory and disk-bound processing, easy adaptation to different data formats, simpler software development and maintenance, and the ability to distribute processing tasks on multi-CPU computers and computer networks.
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        RAS is regulated by the let-7 microRNA family.

        MicroRNAs (miRNAs) are regulatory RNAs found in multicellular eukaryotes, including humans, where they are implicated in cancer. The let-7 miRNA times seam cell terminal differentiation in C. elegans. Here we show that the let-7 family negatively regulates let-60/RAS. Loss of let-60/RAS suppresses let-7, and the let-60/RAS 3'UTR contains multiple let-7 complementary sites (LCSs), restricting reporter gene expression in a let-7-dependent manner. mir-84, a let-7 family member, is largely absent in vulval precursor cell P6.p at the time that let-60/RAS specifies the 1 degrees vulval fate in that cell, and mir-84 overexpression suppresses the multivulva phenotype of activating let-60/RAS mutations. The 3'UTRs of the human RAS genes contain multiple LCSs, allowing let-7 to regulate RAS expression. let-7 expression is lower in lung tumors than in normal lung tissue, while RAS protein is significantly higher in lung tumors, providing a possible mechanism for let-7 in cancer.
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          Biogenesis of small RNAs in animals.

          Small RNAs of 20-30 nucleotides can target both chromatin and transcripts, and thereby keep both the genome and the transcriptome under extensive surveillance. Recent progress in high-throughput sequencing has uncovered an astounding landscape of small RNAs in eukaryotic cells. Various small RNAs of distinctive characteristics have been found and can be classified into three classes based on their biogenesis mechanism and the type of Argonaute protein that they are associated with: microRNAs (miRNAs), endogenous small interfering RNAs (endo-siRNAs or esiRNAs) and Piwi-interacting RNAs (piRNAs). This Review summarizes our current knowledge of how these intriguing molecules are generated in animal cells.
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            Author and article information

            Affiliations
            [1 ]Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
            [2 ]Istituto Nazionale per la Ricerca sul Cancro (IST), Largo R. Benzi, 10; 16132 Genova, Italy
            [3 ]Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, U.K.
            [4 ]Friedrich Miescher Institute for Biomedical Research, P.O. Box 2543, 4002 Basel, Switzerland
            Author notes
            [*]

            equal contributors

            Author Information Reprints and permissions information is available at www.nature.com/reprints. Correspondence and requests for materials should be addressed to M.G.R. ( mrosenfeld@ 123456ucsd.edu ), R.G. ( rgherzi@ 123456ucsd.edu ), or to AR. ( aramos@ 123456nimr.mrc.ac.uk ).
            Journal
            0410462
            6011
            Nature
            Nature
            0028-0836
            1476-4687
            23 April 2009
            20 May 2009
            18 June 2009
            18 December 2009
            : 459
            : 7249
            : 1010-1014
            2768332
            19458619
            10.1038/nature08025
            nihpa105928
            Funding
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Award ID: R37 DK039949-27 ||DK
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Award ID: R37 DK039949-26 ||DK
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