Nucleic Acids Research Advance Access originally published online on July 24, 2008
Nucleic Acids Research 2008 36(15):4902-4912; doi:10.1093/nar/gkn472
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Nucleic Acids Research, 2008, Vol. 36, No. 15 4902-4912
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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The G-quartet containing FMRP binding site in FMR1 mRNA is a potent exonic splicing enhancer
IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U596, CNRS UMR7104, Université Louis Pasteur, Collège de France, Illkirch, F-67400 France
*To whom correspondence should be addressed. Tel: +33 3 8865 3258; Fax: +33 3 5565 3246; Email: moine{at}igbmc.u-strasbg.fr
Received May 9, 2008. Revised June 30, 2008. Accepted July 7, 2008.
The fragile X mental retardation protein (FMRP) is a RNA-binding protein proposed to post-transcriptionally regulate the expression of genes important for neuronal development and synaptic plasticity. We previously demonstrated that FMRP binds to its own FMR1 mRNA via a guanine-quartet (G-quartet) RNA motif. However, the functional effect of this binding on FMR1 expression was not established. In this work, we characterized the FMRP binding site (FBS) within the FMR1 mRNA by a site directed mutagenesis approach and we investigated its importance for FMR1 expression. We show that the FBS in the FMR1 mRNA adopts two alternative G-quartet structures to which FMRP can equally bind. While FMRP binding to mRNAs is generally proposed to induce translational regulation, we found that mutations in the FMR1 mRNA suppressing binding to FMRP do not affect its translation in cellular models. We show instead that the FBS is a potent exonic splicing enhancer in a minigene system. Furthermore, FMR1 alternative splicing is affected by the intracellular level of FMRP. These data suggest that the G-quartet motif present in the FMR1 mRNA can act as a control element of its alternative splicing in a negative autoregulatory loop.
Present address: Céline Schaeffer, Department of Neurobiology and Genetics, Dulbecco Telethon Institute, Molecular Genetics of Renal Disorders Unit, Dibit-San Raffaele Scientific Institute, Milan, Italy
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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