SINEUP non-coding RNA activity depends on specific N6-methyladenosine nucleotides.

Autor:	Pierattini B; Area of Neuroscience, International School for Advanced Studies (SISSA), Trieste, Italy.; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy., D'Agostino S; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy., Bon C; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy., Peruzzo O; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy., Alendar A; The Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK., Codino A; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy., Ros G; Department of Health Sciences and Research Center on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale (UPO), Novara, Italy., Persichetti F; Department of Health Sciences and Research Center on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale (UPO), Novara, Italy., Sanges R; Area of Neuroscience, International School for Advanced Studies (SISSA), Trieste, Italy.; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy., Carninci P; RIKEN Center for Integrative Medical Sciences (IMS), Yokohama 230-0045, Japan.; Human Technopole, 20157 Milan, Italy., Santoro C; Department of Health Sciences and Research Center on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale (UPO), Novara, Italy., Espinoza S; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy.; Department of Health Sciences and Research Center on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale (UPO), Novara, Italy., Valentini P; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy., Pandolfini L; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy., Gustincich S; Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Apr 07; Vol. 32, pp. 402-414. Date of Electronic Publication: 2023 Apr 07 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.04.002
Abstrakt:	SINEUPs are natural and synthetic antisense long non-coding RNAs (lncRNAs) selectively enhancing target mRNAs translation by increasing their association with polysomes. This activity requires two RNA domains: an embedded inverted SINEB2 element acting as effector domain, and an antisense region, the binding domain, conferring target selectivity. SINEUP technology presents several advantages to treat genetic (haploinsufficiencies) and complex diseases restoring the physiological activity of diseased genes and of compensatory pathways. To streamline these applications to the clinic, a better understanding of the mechanism of action is needed. Here we show that natural mouse SINEUP AS Uchl1 and synthetic human miniSINEUP-DJ-1 are N 6 -methyladenosine (m 6 A) modified by METTL3 enzyme. Then, we map m 6 A-modified sites along SINEUP sequence with Nanopore direct RNA sequencing and a reverse transcription assay. We report that m 6 A removal from SINEUP RNA causes the depletion of endogenous target mRNA from actively translating polysomes, without altering SINEUP enrichment in ribosomal subunit-associated fractions. These results prove that SINEUP activity requires an m 6 A-dependent step to enhance translation of target mRNAs, providing a new mechanism for m 6 A translation regulation and strengthening our knowledge of SINEUP-specific mode of action. Altogether these new findings pave the way to a more effective therapeutic application of this well-defined class of lncRNAs. Competing Interests: S.G., C.S., and P.C. are co-founders of Transine Therapeutics. (© 2023 The Author(s).)
Databáze:	MEDLINE
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