Fragile X mental retardation protein recognizes a G quadruplex structure within the survival motor neuron domain containing 1 mRNA 5′-UTR. Issue 8 (14th June 2017)

• Record Type: Journal Article
• Authors: McAninch, Damian S.; Heinaman, Ashley M.; Lang, Cara N.; Moss, Kathryn R.; Bassell, Gary J.; Rita Mihailescu, Mihaela; Evans, Timothy L.
• Is Part Of: Molecular bioSystems. Volume 13:Issue 8(2017)
• Page Start: 1448
• Page End: 1457
• Publication Date: 2017-06-14
• Subjects: Molecular biology -- Periodicals; Biochemistry -- Periodicals; 571.7405
• DOI: 10.1039/c7mb00070g
• Languages: English
• ISSNs: 1742-206X

Abstract

Abstract : SMNDC1 mRNA adopts a 5′-UTR G quadruplex structure recognized specifically by FMRP, potentially affecting spliceosome assembly in FXS. Abstract : 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.