Inosine-containing dsRNA binds a stress-granule-like complex and downregulates gene expression in trans.
Long double-stranded RNAs (dsRNAs) may undergo extensive modification (hyperediting) by adenosine deaminases that act on RNA (ADARs), where up to 50% of adenosine (A) residues are changed to inosine (I). Traditionally, consequences of A-to-I editing were thought to be limited to modified RNA itself. We show here, however, that hyperedited dsRNA (I-dsRNA) is able to downregulate gene expression in trans. Furthermore, we show that both endogenous expression and reporter gene expression were substantially reduced in the presence of I-dsRNA. This was due to a reduction in reporter mRNA levels and also translation inhibition. Importantly, we show that I-dsRNA interferes with translation initiation. We also show that I-dsRNA specifically binds a stress-granule-like complex. Stress granules (SGs) are important for translational silencing during stress. Finally, we propose a model whereby editing by ADARs results in downregulation of gene expression via SG formation.
Scadden
A D J
AD
Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK. adjs@bioc.cam.ac.uk
D015536:Down-Regulation; D017930:Genes, Reporter; D005914:Globins / Q000032:analysis; D049452:Green Fluorescent Proteins / Q000032:analysis; D006367:HeLa Cells; D006801:Humans; D007288:Inosine / Q000737:chemistry; D049409:Luciferases, Firefly / Q000032:analysis; D049410:Luciferases, Renilla / Q000032:analysis; D008957:Models, Genetic; D014176:Protein Biosynthesis; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism
D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D049452:Green Fluorescent Proteins; D007288:Inosine; D005914:Globins; D049410:Luciferases, Renilla; D049409:Luciferases, Firefly