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

Abstract

Consistent with the role of microRNAs (miRNAs) in down-regulating gene expression by reducing translation and/or stability of target mRNAs1, the levels of specific miRNAs are important for correct embryonic development and have been linked to several forms of cancer2-4. 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 complexes5-8, 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 decay9,10. 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.

Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer

“…Lin28 is known to block the production of a group of microRNAs, including let-7 microRNAs, which have been implicated previously in the regulation of cell proliferation and differentiation (Bussing et al, 2008;Heo et al, 2009;Trabucchi et al, 2009). The observed growth inhibition following Lin28 repression is likely the result, at least in part, of a restoration in let-7 microRNA expression, which has been linked to a translational blockade of target mRNAs involved in promoting cell cycle progression (Bussing et al, 2008).…”

“…It has been shown to block the processing of let-7 microRNAs (Heo et al, 2008;Newman et al, 2008;Rybak et al, 2008;Viswanathan et al, 2008) as well as a handful of other microRNAs (Heo et al, 2009;Trabucchi et al, 2009). In addition, Lin28 has been reported by us and others to bind to a specific subset of mRNAs, including those for IGF-2, Oct4, and several cell cycle-related factors, thereby modulating their translation (Polesskaya et al, 2007;Qiu et al, 2009;.…”

KSRP/FUBP2 Is a Binding Protein of GO-Y086, a Cytotoxic Curcumin Analogue

“…KSRP/FUBP2 is implicated in a variety of cellular processes, including splicing in the nucleus, mRNA decay, maturation of miRNA, and transcriptional control of proto-oncogenes such as c-myc. [13][14][15][16] The domain structure of KSRP/FUBP2 consists of a PG-rich amino-terminus, four KH-type nucleic acid-binding domains, and a Q-rich carboxy (C)-terminus ( Figure 4A). 17 To identify the GO-Y086-binding site on KSRP/FUBP2, pull down assays were carried out using different GFP-tagged deletion mutants of KSRP/FUBP2 ( Figure 4B).…”

Identification of Loop Nucleotide Polymorphisms Affecting MicroRNA Processing and Function

“…Our findings strongly support the latter model, and suggest that further analyses are required to precisely dissect the role of the pri-miRNA loop in miRNA processing in vivo. Although several regulatory proteins have been demonstrated to bind to pri/pre-miRNA loops and affect the production of mature miRNA (Heo et al, 2008;2009;Michlewski and Caceres, 2010;Newman et al, 2008;Trabucchi et al, 2009;Viswanathan et al, 2008) and conserved loop sequences are required for the interaction between these regulatory factors (Heo et al, 2009;Newman et al, 2008), none of these proteins have been shown to be involved in the regulation of the processing accuracy of the mature miRNA 5′ seed region. Additionally, 5′ end polymorphisms have been detected in miRNA profiles of CD8 T cells (Wu et al, 2007), but there is little evidence to explain the heterogeneity of the 5′ end of mature miRNAs.…”