The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs

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Abstract
As small RNAs exert profound effects on development and regulation of gene expression, their own expression must be similarly constrained to the right level in the right cell at the right time. A collaboration between the labs of Michael Rosenfeld and Witold Filipowicz reports that the RNA-binding protein KSRP (KH-type splicing regulatory protein) regulates the precursor processing of a subset of microRNAs. If this regulatory mechanism is disrupted, effects can be seen on proliferation, differentiation and apoptosis. Thus KSRP is involved in both mRNA turnover and in promoting mRNA expression. This work has uncovered a further level of complexity in the regulation of gene expression by mi-RNA. MicroRNAs (miRNAs) have a role in down-regulating gene expression, and the levels of specific miRNAs are important for correct embryonic development; however, the mechanisms by which this is regulated are unknown. The splicing regulatory protein, KSRP, is now found to regulate the precursor processing of a subset of miRNAs, and its disruption leads to effects on proliferation, differentiation and apoptosis. 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.