Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway

Tina Uroda; Eleni Anastasakou; Annalisa Rossi; Jean Marie Teulon; Jean-Luc  Pellequer; Paolo Annibale; Ombeline Pessey; Alberto Inga; Isabel Chillón; Marco Marcia

doi:10.1016/j.molcel.2019.07.025

Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway

Tina Uroda, Eleni Anastasakou, Annalisa Rossi, Jean Marie Teulon, Jean-Luc Pellequer, Paolo Annibale, Ombeline Pessey, Alberto Inga, Isabel Chillón^*, Marco Marcia

^*Corresponding author for this work

School of Physics and Astronomy

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	982-995
Number of pages	24
Journal	Molecular Cell
Volume	75
Issue number	5
Early online date	20 Aug 2019
DOIs	https://doi.org/10.1016/j.molcel.2019.07.025
Publication status	Published - 5 Sept 2019

Keywords

Alternative splicing
Atomic force microscopy
Cell cycle regulation
Epigenetics
Imprinting
p53 stress response
Pituitary adenoma
RNA evolution
RNA pseudoknots
RNA structure

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10.1016/j.molcel.2019.07.025Licence: CC BY

Uroda_2019_Mol-Cell_Conserved-pseudoknots-lncRNA-MEG3_CC
Copyright © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license.
Final published version, 5.19 MBLicence: CC BY

Cite this

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title = "Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway",

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 = "Alternative splicing, Atomic force microscopy, Cell cycle regulation, Epigenetics, Imprinting, p53 stress response, Pituitary adenoma, RNA evolution, RNA pseudoknots, RNA structure",

author = "Tina Uroda and Eleni Anastasakou and Annalisa Rossi and Teulon, {Jean Marie} and Jean-Luc Pellequer and Paolo Annibale and Ombeline Pessey and Alberto Inga and Isabel Chill{\'o}n and Marco Marcia",

note = "Funding 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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T1 - Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway

AU - Uroda, Tina

AU - Anastasakou, Eleni

AU - Rossi, Annalisa

AU - Teulon, Jean Marie

AU - Pellequer, Jean-Luc

AU - Annibale, Paolo

AU - Pessey, Ombeline

AU - Inga, Alberto

AU - Chillón, Isabel

AU - Marcia, Marco

N1 - Funding 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.

PY - 2019/9/5

Y1 - 2019/9/5

N2 - 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.

AB - 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.

KW - Alternative splicing

KW - Atomic force microscopy

KW - Cell cycle regulation

KW - Epigenetics

KW - Imprinting

KW - p53 stress response

KW - Pituitary adenoma

KW - RNA evolution

KW - RNA pseudoknots

KW - RNA structure

U2 - 10.1016/j.molcel.2019.07.025

DO - 10.1016/j.molcel.2019.07.025

M3 - Article

C2 - 31444106

AN - SCOPUS:85071560684

SN - 1097-2765

VL - 75

SP - 982

EP - 995

JO - Molecular Cell

JF - Molecular Cell

IS - 5

ER -

Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway

Abstract

Keywords

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