Involvement of FMRP in Primary MicroRNA Processing via Enhancing Drosha Translation

Wan, Rui-Ping; Zhou, Lin-Tao; Yang, Haixuan; Zhou, Yongting; Ye, Shun-Hua; Zhao, Qi‐Hua; Gao, Mei-Mei; Liao, Wei‐Ping; Yi, Yong‐Hong; Long, Yue-Sheng

doi:10.1007/s12035-016-9855-9

Cited by 21 publications

(8 citation statements)

References 65 publications

(87 reference statements)

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“…Interestingly, we found that the FMRP-phosphomimic S500D binds to miR-125a (Fig 5B), whereas the unphosphoryated protein does not (Fig 5A), even at high protein: RNA concentrations (S4 Fig). This is a novel finding, as previously it has been shown that phosphorylated FMRP associates with precursor microRNAs [56, 57], and that FMRP can anneal mature miRNAs onto their mRNA targets [37], but not that depending on its phosphorylation status FMRP could function as a switch in binding mature miRNAs. The binding of miR-125a is specific, as an unrelated miRNA, miR-122, is not bound by FMRP S500D (Fig 5E).…”

Section: Discussionmentioning

confidence: 58%

FMRP - G-quadruplex mRNA - miR-125a interactions: Implications for miR-125a mediated translation regulation of PSD-95 mRNA

et al. 2019

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Fragile X syndrome, the most common inherited form of intellectual disability, is caused by the CGG trinucleotide expansion in the 5’-untranslated region of the Fmr1 gene on the X chromosome, which silences the expression of the fragile X mental retardation protein (FMRP). FMRP has been shown to bind to a G-rich region within the PSD-95 mRNA, which encodes for the postsynaptic density protein 95, and together with microRNA-125a to mediate the reversible inhibition of the PSD-95 mRNA translation in neurons. The miR-125a binding site within the PSD-95 mRNA 3’-untranslated region (UTR) is embedded in a G-rich region bound by FMRP, which we have previously demonstrated folds into two parallel G-quadruplex structures. The FMRP regulation of PSD-95 mRNA translation is complex, being mediated by its phosphorylation. While the requirement for FMRP in the regulation of PSD-95 mRNA translation is clearly established, the exact mechanism by which this is achieved is not known. In this study, we have shown that both unphosphorylated FMRP and its phosphomimic FMRP S500D bind to the PSD-95 mRNA G-quadruplexes with high affinity, whereas only FMRP S500D binds to miR-125a. These results point towards a mechanism by which, depending on its phosphorylation status, FMRP acts as a switch that potentially controls the stability of the complex formed by the miR-125a-guided RNA induced silencing complex (RISC) and PSD-95 mRNA.

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Section: Discussionmentioning

confidence: 58%

FMRP - G-quadruplex mRNA - miR-125a interactions: Implications for miR-125a mediated translation regulation of PSD-95 mRNA

et al. 2019

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“…Recently, in a FXS mice model, FMRP was shown to participate in pri-miRNA processing by upregulating DROSHA expression at the translational level. Loss of FMRP was associated with accumulation of specific pri-miRNAs and reduction of pre-miRNAs (Wan et al, 2017).…”

Section: Non-coding Rna Mediated Mechanisms In Fxs Pathophysiologymentioning

confidence: 99%

Non-coding RNA in Fragile X Syndrome and Converging Mechanisms Shared by Related Disorders

Zhou

Sun

et al. 2019

Front. Genet.

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Fragile X syndrome (FXS) is one of the most common forms of hereditary intellectual disability. It is also a well-known monogenic cause of autism spectrum disorders (ASD). Repetitive trinucleotide expansion of CGG repeats in the 5′-UTR of FMR1 is the pathological mutation. Full mutation CGG repeats epigenetically silence FMR1 and thus lead to the absence of its product, fragile mental retardation protein (FMRP), which is an indispensable translational regulator at synapsis. Loss of FMRP causes abnormal neural morphology, dysregulated protein translation, and distorted synaptic plasticity, giving rise to FXS phenotypes. Non-coding RNAs, including siRNA, miRNA, and lncRNA, are transcribed from DNA but not meant for protein translation. They are not junk sequence but play indispensable roles in diverse cellular processes. FXS is the first neurological disorder being linked to miRNA pathway dysfunction. Since then, insightful knowledge has been gained in this field. In this review, we mainly focus on how non-coding RNAs, especially the siRNAs, miRNAs, and lncRNAs, are involved in FXS pathogenesis. We would also like to discuss several potential mechanisms mediated by non-coding RNAs that may be shared by FXS and other related disorders.

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“…4b). Moreover, When an exogenous vector pFRT-TODestFLAGHAhFMRPiso13334, purchased from Addgene (Addgene Plasmid #48690) with Drosha expression enhancing ability, was co-transfected with msgRNA-ALA plasmid, the relative LIG4 expression declined to about 50% (Fig. 4b),…”

Section: Resultsmentioning

confidence: 99%

Multiplex CRISPR/Cas9-based genome engineering enhanced by Drosha-mediated sgRNA-shRNA structure

Yan

Xing

et al. 2016

Sci Rep

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The clustered regularly interspaced short palindromic repeats (CRISPR) system has recently been developed into a powerful genome-editing technology, as it requires only two key components (Cas9 protein and sgRNA) to function and further enables multiplex genome targeting and homology-directed repair (HDR) based precise genome editing in a wide variety of organisms. Here, we report a novel and interesting strategy by using the Drosha-mediated sgRNA-shRNA structure to direct Cas9 for multiplex genome targeting and precise genome editing. For multiplex genome targeting assay, we achieved more than 9% simultaneous mutant efficiency for 3 genomic loci among the puromycin-selected cell clones. By introducing the shRNA against DNA ligase IV gene (LIG4) into the sgRNA-shRNA construct, the HDR-based precise genome editing efficiency was improved as more than 2-fold. Our works provide a useful tool for multiplex and precise genome modifying in mammalian cells.

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Involvement of FMRP in Primary MicroRNA Processing via Enhancing Drosha Translation

Cited by 21 publications

References 65 publications

FMRP - G-quadruplex mRNA - miR-125a interactions: Implications for miR-125a mediated translation regulation of PSD-95 mRNA

FMRP - G-quadruplex mRNA - miR-125a interactions: Implications for miR-125a mediated translation regulation of PSD-95 mRNA

Non-coding RNA in Fragile X Syndrome and Converging Mechanisms Shared by Related Disorders

Multiplex CRISPR/Cas9-based genome engineering enhanced by Drosha-mediated sgRNA-shRNA structure

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