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

Tina Uroda (1) , Eleni Anastasakou (1) , Annalisa Rossi (2) , Jean-Marie Teulon (3) , Jean-Luc Pellequer (3) , Paolo Annibale (4) , Ombeline Pessey (1) , Alberto Inga (2) , Isabel Chillón (1) , Marco Marcia (1)

1 EMBL - European Molecular Biology Laboratory [Grenoble]
2 UNITN - Università degli Studi di Trento = University of Trento
3 IBS - UMR 5075 - Institut de biologie structurale
4 MDC - Max Delbrück Center for Molecular Medicine [Berlin]

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.

Domains: Structural Biology [q-bio.BM]

Tina Uroda, Eleni Anastasakou, Annalisa Rossi, Jean-Marie Teulon, Jean-Luc Pellequer, et al.. Conserved Pseudoknots in lncRNA MEG3 Are Essential for Stimulation of the p53 Pathway. Molecular Cell, 2019, 75, pp.1-14. ⟨10.1016/j.molcel.2019.07.025⟩. ⟨hal-02268983⟩