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RNA editing with endogenous ADARs

Merkle, T. et al. Nat. Biotechnol. 37, 133–138 (2019).

Making changes in the genome after double-strand breaks in the DNA bears the risk of unintended mutations. Making changes by editing RNA, in contrast, involves no such breaks and is thus considered a safer method. Merkle et al. improve site-directed RNA editing by no longer relying on overexpression of the enzyme needed to introduce a base change, adenosine deaminase acting on RNA (ADAR), and instead recruiting endogenous enzymes. Their RESTORE method recruits the ADAR via a bipartite antisense oligo (ASO): an optimized hairpin binds to the enzyme, and a single-stranded sequence with chemical modifications binds the complementary RNA sequence of interest. The researchers show editing of several endogenous transcripts in cultured cell lines and disease-relevant loci in human primary cells. Off-target analysis by RNA-seq demonstrated high specificity of editing. While this work focuses on ADAR1, ASOs could be further modified to recruit other ADAR isoforms.

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Correspondence to Nicole Rusk.

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Rusk, N. RNA editing with endogenous ADARs. Nat Methods 16, 285 (2019).

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