Abstract
Consistent with the role of microRNAs (miRNAs) in down-regulating gene expression by reducing the translation and/or stability of target messenger RNAs1, the levels of specific miRNAs are important for correct embryonic development and have been linked to several forms of cancer2,3,4. 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 complexes5,6,7,8, respectively, remain largely unknown. The KH-type splicing regulatory protein (KSRP, also known as KHSRP) interacts with single-strand AU-rich-element-containing mRNAs and is a key mediator of mRNA decay9,10. Here we show in mammalian cells 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 of the target miRNA precursors and promotes their maturation. This mechanism is required for specific changes in target mRNA expression that affect 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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Acknowledgements
We thank V. Narry Kim, T. C. Hobman, I. G. Macara, D. Srivastava and J. G. Belasco for reagents, G. Corte for sharing laboratory facilities and critical reading, Y. T. Liu for use of the microarray facility, M. Ponassi and C. Nelson for technical assistance, I. Diaz-Moreno, M. Doyle, S. Martin and D. Hollingworth for discussions and reagents, and A. Pasquinelli and A. De Flora for comments and discussions. Part of the studies has been conducted in the laboratories and facilities of the Centro Biotecnologie Avanzate (CBA, Genova, Italy). M.G.R. is an investigator with the Howard Hughes Medical Institute. M.T. is supported by a post-doctoral fellowship from the Italian Telethon Foundation. This work has been partly supported by grants from Italian ISS (527B/2B/6), AIRC and CIPE 2007 to R.G., ISS (526D/39) to P.B., the EC FP6 Program Sirocco to W.F. and NIH grants DK018477, DK39949 and HL065445 to M.G.R. P.B. is recipient of a Senior Scholar Consultancy grant from AICF. Structural work on KSRP–RNA interaction is supported by grant WT022088MA from the Wellcome Trust. NMR spectra were recorded at the MRC Biomedical NMR Centre, London. The Friedrich Miescher Institute is supported by the Novartis Research Foundation.
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Trabucchi, M., Briata, P., Garcia-Mayoral, M. et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature 459, 1010–1014 (2009). https://doi.org/10.1038/nature08025
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DOI: https://doi.org/10.1038/nature08025
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