Deciphering the principles of the RNA editing code via large-scale systematic probing

Uzonyi, Anna; Nir, Ronit; Shliefer, Ofir; Stern-Ginossar, Noam; Antebi, Yaron E.; Stelzer, Yonatan; Levanon, Erez Y.; Schwartz, Schraga

doi:10.1016/j.molcel.2021.03.024

Cited by 24 publications

(30 citation statements)

References 57 publications

(60 reference statements)

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“…[40][41][42] The principle of the RNA editing code has been unlocked recently for ADAR1 using a massively parallel synthetic approach. [43] Certain local sequence motifs and minor structural disruption can be favorably edited, which can further propagate the editing events along the dsRNA in a recursive manner. RNA editing is critical to disrupt the structure of endogenous dsRNA and hence to prevent their recognition as foreign nucleic acids by the host immune system.…”

Section: Introductionmentioning

confidence: 99%

Functional interplay within the epitranscriptome: Reality or fiction?

2021

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RNA modifications have recently emerged as an important regulatory layer of gene expression. The most prevalent and reversible modification on messenger RNA (mRNA), N6‐methyladenosine, regulates most steps of RNA metabolism and its dysregulation has been associated with numerous diseases. Other modifications such as 5‐methylcytosine and N1‐methyladenosine have also been detected on mRNA but their abundance is lower and still debated. Adenosine to inosine RNA editing is widespread on coding and non‐coding RNA and can alter mRNA decoding as well as protect against autoimmune diseases. 2′‐O‐methylation of the ribose and pseudouridine are widespread on ribosomal and transfer RNA and contribute to proper RNA folding and stability. While the understanding of the individual role of RNA modifications has now reached an unprecedented stage, still little is known about their interplay in the control of gene expression. In this review we discuss the examples where such interplay has been observed and speculate that with the progress of mapping technologies more of those will rapidly accumulate.

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Section: Introductionmentioning

confidence: 99%

Functional interplay within the epitranscriptome: Reality or fiction?

2021

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“…Interestingly, the length of complementarity, structure formed, and mode of enzyme recruitment varies between the systems discussed. This resembles the situation found in vivo , where the structures of endogenous editing substrates vary widely and clearly depend on the type of enzyme recruited [ 68 , 69 ] . Thus, guide RNA design will most likely need to be optimized for each substrate individually.…”

Section: Optimizing Rna Designmentioning

confidence: 62%

Site-directed RNA editing: recent advances and open challenges

Khosravi¹,

Jantsch²

2021

RNA Biology

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RNA editing by cytosine and adenosine deaminases changes the identity of the edited bases. While cytosines are converted to uracils, adenines are converted to inosines. If coding regions of mRNAs are affected, the coding potential of the RNA can be changed, depending on the codon affected. The recoding potential of nucleotide deaminases has recently gained attention for their ability to correct genetic mutations by either reverting the mutation itself or by manipulating processing steps such as RNA splicing. In contrast to CRISPR-based DNA-editing approaches, RNA editing events are transient in nature, therefore reducing the risk of long-lasting inadvertent side-effects. Moreover, some RNA-based therapeutics are already FDA approved and their use in targeting multiple cells or organs to restore genetic function has already been shown. In this review, we provide an overview on the current status and technical differences of site-directed RNA-editing approaches. We also discuss advantages and challenges of individual approaches.

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“…Adenosine-to-inosine (A-to-I) editing mediated by enzymes of the Adenosine Deaminase Acting on dsRNA (ADAR) family, produce posttranscriptional conversions in RNAs with double-stranded structures ( 10 ), a phenomenon relevant in natural and experimental viral infections ( 11 ). Although the rules of ADAR1 substrate selection are partially unclear, a massively parallel synthetic approach provided new insights in determining the targets’ editability ( 12 ). Mechanistically, dysregulation of ADAR editing in vertebrates has been associated with cancer progression, autoimmune diseases, and increased inflammation, whereas during viral infection the pro- or antiviral role of ADAR hyper-editing depends on the host–virus combination ( 13 ).…”

Section: Opinion/hypothesismentioning

confidence: 99%