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Mol Cell. 2019 Sep 5;75(5):982-995.e9. doi: 10.1016/j.molcel.2019.07.025. Epub 2019 Aug 20.

Conserved Pseudoknots in lncRNA MEG3 Are Essential for Stimulation of the p53 Pathway.

Author information

1
European Molecular Biology Laboratory (EMBL) Grenoble, 71 Avenue des Martyrs, Grenoble 38042, France.
2
Department CIBIO, University of Trento, via Sommarive 9, 38123 Povo (Trento), Italy.
3
Université Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS), 38000 Grenoble, France.
4
Max Delbruck Center, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
5
European Molecular Biology Laboratory (EMBL) Grenoble, 71 Avenue des Martyrs, Grenoble 38042, France. Electronic address: ichillon@embl.fr.
6
European Molecular Biology Laboratory (EMBL) Grenoble, 71 Avenue des Martyrs, Grenoble 38042, France. Electronic address: mmarcia@embl.fr.

Abstract

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.

KEYWORDS:

RNA evolution; RNA pseudoknots; RNA structure; alternative splicing; atomic force microscopy; cell cycle regulation; epigenetics; imprinting; p53 stress response; pituitary adenoma

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