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Comprehensive analysis of translation from overexpressed circular RNAs reveals pervasive translation from linear transcripts

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Item Type:Article
Title:Comprehensive analysis of translation from overexpressed circular RNAs reveals pervasive translation from linear transcripts
Creators Name:Ho-Xuan, H. and Glažar, P. and Latini, C. and Heizler, K. and Haase, J. and Hett, R. and Anders, M. and Weichmann, F. and Bruckmann, A. and Van den Berg, D. and Hüttelmaier, S. and Rajewsky, N. and Hackl, C. and Meister, G.
Abstract:Circular RNAs (circRNAs) encompass a widespread and conserved class of RNAs, which are generated by back-splicing of downstream 5' to upstream 3' splice sites. CircRNAs are tissue-specific and have been implicated in diseases including cancer. They can function as sponges for microRNAs (miRNAs) or RNA binding proteins (RBPs), for example. Moreover, some contain open reading frames (ORFs) and might be translated. The functional relevance of such peptides, however, remains largely elusive. Here, we report that the ORF of circZNF609 is efficiently translated when expressed from a circZNF609 overexpression construct. However, endogenous proteins could not be detected. Moreover, initiation of circZNF609 translation is independent of m(6)A-generating enzyme METTL3 or RNA sequence elements such as internal ribosome entry sites (IRESs). Surprisingly, a comprehensive mutational analysis revealed that deletion constructs, which are deficient in producing circZNF609, still generate the observed protein products. This suggests that the apparent circZNF609 translation originates from trans-splicing by-products of the overexpression plasmids and underline that circRNA overexpression constructs need to be evaluated carefully, particularly when functional studies are performed.
Keywords:Base Sequence, Circular RNA, Gene Expression Regulation, HEK293 Cells, Internal Ribosome Entry Sites, Methyltransferases, MicroRNAs, Protein Biosynthesis, RNA Splice Sites, RNA-Binding Proteins
Source:Nucleic Acids Research
Publisher:Oxford University Press
Page Range:10368-10382
Date:9 October 2020
Official Publication:https://doi.org/10.1093/nar/gkaa704
PubMed:View item in PubMed

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