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Author Notes:

Mihaela Mihailescu: mihailescum@duq.edu

The authors have declared that no competing interests exist.

Subjects:

Research Funding:

This work was supported by the National Institutes of Health (https://www.nih.gov) grants 9R15GM127307-04 to M.R.M.; and R01MH109026 to G.J.B.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MENTAL-RETARDATION PROTEIN
  • RECEPTOR-DEPENDENT TRANSLATION
  • FRAGILE-X-SYNDROME
  • G-QUARTET
  • MOLECULAR INSIGHTS
  • BINDING-SITE
  • MOUSE MODEL
  • KH DOMAINS
  • PHOSPHORYLATION
  • 2-AMINOPURINE

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

Journal Title:

PLoS ONE

Volume:

Volume 14, Number 5

Publisher:

, Pages e0217275-e0217275

Type of Work:

Article | Final Publisher PDF

Abstract:

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.

Copyright information:

© 2019 DeMarco et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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