FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

Zhang, Yang; Gaetano, Christian M.; Williams, Kathryn R.; Bassell, Gary J.; Mihailescu, Mihaela‐Rita

doi:10.1080/15476286.2014.996464

Cited by 53 publications

(75 citation statements)

References 62 publications

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“…In the former case, the long 5 ′ UTR expansion forms a CpG island, resulting in transcriptional silencing and therefore reduced levels of FMRP. Supporting the significance of the G-Qs, FMRP is capable of binding transcripts containing them (Darnell et al 2001;Vasilyev et al 2015), which can facilitate their translocation, in some cases, to synapses (Zhang et al 2014;Stefanovic et al 2015). In FXTAS patients, FMR1 is not completely silenced, and the expansion is actively transcribed into a repeat-containing RNA that has been reported to bind multiple RBPs, such as hnRNP A2/B1, MBNL1 (Iwahashi et al 2006), Sam68 (Sellier et al 2010), Drosha, DGCR8 (Sellier et al 2013), and more (Galloway and Nelson 2009).…”

Section: Rna-centric Mechanisms In C9orf72 Als-ftdmentioning

confidence: 97%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

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Section: Rna-centric Mechanisms In C9orf72 Als-ftdmentioning

confidence: 97%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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“…The FMRP RGG box peptide (Table 1) and the hepatitis C virus (HCV) core peptide (combined sequences of amino acids 2–23 and 38–74) 24, 64 were chemically synthesized and purified by the Peptide Synthesis Unit at the University of Pittsburgh, Center for Biotechnology and Bioengineering.…”

Section: Methodsmentioning

confidence: 99%

“…1 Despite their potentially major roles in mRNA translation regulation, only a limited number of these predicted G quadruplexes have been structurally and thermodynamically characterized. 4–6, 8, 9, 19, 24, 27–30 The prevalence of G quadruplexes in the 5′-UTR suggests a role in the regulation of translation considering the advantageous control of the process at or near its point of initiation. 1 Additionally, some 5′-UTR G quadruplex structures have been shown to inhibit translation while others promote translation, suggesting a complex form of regulation that requires further investigation to elucidate.…”

Section: Introductionmentioning

confidence: 99%

“…49, 50 FMRP has been shown to use its RGG box domain to bind mRNA targets that form G quadruplex structures (Table 1). 19, 24, 27–29, 33, 34, 51, 52 However, with the exception of the 5′-UTRs from microtubule associated protein 1B (MAP1B) mRNA, 27, 40 the protein phosphatase 2A catalytic subunit mRNA, 39 and the hASH1 mRNA 5′-UTR, 48 characterization of the FMRP RGG box binding G quadruplex structures has focused on coding region and 3′-UTR locations. 19, 24, 28, 29, 34 …”

Section: Introductionmentioning

confidence: 99%

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Fragile X mental retardation protein recognizes a G quadruplex structure within the survival motor neuron domain containing 1 mRNA 5′-UTR

et al. 2017

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G quadruplex structures have been predicted by bioinformatics to form in the 5′- and 3′-untranslated regions (UTRs) of several thousand mature mRNAs and are believed to play a role in translation regulation. Elucidation of these roles has primarily been focused on the 3′-UTR, with limited focus on characterizing the G quadruplex structures and functions in the 5′-UTR. Investigation of the affinity and specificity of RNA binding proteins for 5′-UTR G quadruplexes and the resulting regulatory effects have also been limited. Among the mRNAs predicted to form a G quadruplex structure within the 5′-UTR is the survival motor neuron domain containing 1 (SMNDC1) mRNA, encoding a protein that is critical to the spliceosome. Additionally, this mRNA has been identified as a potential target of the fragile X mental retardation protein (FMRP), whose loss of expression leads to fragile X syndrome. FMRP is an RNA binding protein involved in translation regulation that has been shown to bind mRNA targets that form G quadruplex structures. In this study we have used biophysical methods to investigate G quadruplex formation in the 5′-UTR of SMNDC1 mRNA and analyzed its interactions with FMRP. Our results show that SMNDC1 mRNA 5′-UTR forms an intramolecular, parallel G quadruplex structure comprised of three G quartet planes, which is bound specifically by FMRP both in vitro and in mouse brain lysates. These findings suggest a model by which FMRP might regulate the translation of a subset of its mRNA targets by recognizing the G quadruplex structure present in their 5′-UTR, and affecting their accessibility by the protein synthesis machinery.

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“…To the best of our knowledge, till date there is no such database available that is solely dedicated to the proteins interacting with nucleic acids forming G-quadruplex structures. Herein, we report the first database that provides detailed information for various proteins that binds to G-quadruplex structures forming DNA and/or RNA such as NCL1618, RHAU1920, BLM Helicase21, UP122, TPP123, IGF224, FMRP25, SRSF116, NOA126, etc. These comprehensive details available on a single source would allow the database users to get all the relevant information in one click that ease drug discovery process in a rational manner.…”

mentioning

confidence: 99%

G4IPDB: A database for G-quadruplex structure forming nucleic acid interacting proteins

Mishra

Tawani

Mishra

et al. 2016

Sci Rep

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Nucleic acid G-quadruplex structure (G4) Interacting Proteins DataBase (G4IPDB) is an important database that contains detailed information about proteins interacting with nucleic acids that forms G-quadruplex structures. G4IPDB is the first database that provides comprehensive information about this interaction at a single platform. This database contains more than 200 entries with details of interaction such as interacting protein name and their synonyms, their UniProt-ID, source organism, target name and its sequences, ∆Tm, binding/dissociation constants, protein gene name, protein FASTA sequence, interacting residue in protein, related PDB entries, interaction ID, graphical view, PMID, author’s name and techniques that were used to detect their interactions. G4IPDB also provides an efficient web-based “G-quadruplex predictor tool” that searches putative G-quadruplex forming sequences simultaneously in both sense and anti-sense strands of the query nucleotide sequence and provides the predicted G score. Studying the interaction between proteins and nucleic acids forming G-quadruplex structures could be of therapeutic significance for various diseases including cancer and neurological disease, therefore, having detail information about their interactions on a single platform would be helpful for the discovery and development of novel therapeutics. G4IPDB can be routinely updated (twice in year) and freely available on http://bsbe.iiti.ac.in/bsbe/ipdb/index.php.

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FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

Cited by 53 publications

References 62 publications

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

Fragile X mental retardation protein recognizes a G quadruplex structure within the survival motor neuron domain containing 1 mRNA 5′-UTR

G4IPDB: A database for G-quadruplex structure forming nucleic acid interacting proteins

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