Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway
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Long non-coding RNAs (lncRNAs) are key regulatory molecules, but unlike with other RNAs, the direct link between their tertiary structure motifs and their function has proven elusive. Here we report structural and functional studies of human maternally expressed gene 3 (MEG3), a tumor suppressor lncRNA that modulates the p53 response. We found that, in an evolutionary conserved region of MEG3, two distal motifs interact by base complementarity to form alternative, mutually exclusive pseudoknot structures (“kissing loops”). Mutations that disrupt these interactions impair MEG3-dependent p53 stimulation in vivo and disrupt MEG3 folding in vitro. These findings provide mechanistic insights into regulation of the p53 pathway by MEG3 and reveal how conserved motifs of tertiary structure can regulate lncRNA biological function.
Uroda , T , Anastasakou , E , Rossi , A , Teulon , J M , Pellequer , J-L , Annibale , P , Pessey , O , Inga , A , Chillón , I & Marcia , M 2019 , ' Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway ' , Molecular Cell , vol. 75 , no. 5 , pp. 982-995 . https://doi.org/10.1016/j.molcel.2019.07.025
Copyright © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license.
DescriptionFunding Information: Work in the Marcia lab is partly funded by the Agence Nationale de la Recherche (ANR-15-CE11-0003-01), the Agence Nationale de Recherche sur le Sida et les H?patites Virales (ANRS, ECTZ18552), and ITMO Cancer (18CN047-00). The Marcia lab uses the platforms of the Grenoble Instruct Center (ISBG UMS 3518 CNRS-CEA-UJF-EMBL) with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX-49-01) within the Grenoble Partnership for Structural Biology (PSB). IBS acknowledges integration into the Interdisciplinary Research Institute of Grenoble (IRIG, CEA). This work acknowledges the AFM platform at the IBS.
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