CRISPR-based tools have revolutionized our ability to target disease-linked genetic mutations. CRISPR technology comprises a growing family of tools that can manipulate genes and their expression, including by targeting DNA with the enzymes Cas9 and Cas12, and by targeting RNA with the enzyme Cas13. This collection offers different strategies for tackling mutations. Targeting disease-linked mutations in RNA, which is relatively short-lived, would avoid making permanent changes to the genome. In addition, some cell types, such as neurons, are difficult to edit using CRISPR/Cas9-mediated editing, and new strategies are needed to treat devastating diseases that affect the brain. McGovern Institute Investigator and Broad Institute of MIT and Harvard core member Feng Zhang (photo), PhD, and his team have now developed one such strategy, called RESCUE (RNA Editing for Specific C to U Exchange), which they describe in an article published in the July 26, 2019 issue of Science. The article is titled “A Cytosine Deaminase for Programmable Single-Base RNA Editing.” Dr. Zhang and his team, including first co-authors Omar Abudayyeh, PhD, and Jonathan Gootenberg, PhD, (both now McGovern Fellows), made use of a deactivated Cas13 to guide RESCUE to targeted cytosine bases on RNA transcripts, and used a novel, evolved, programmable enzyme to convert unwanted cytosine into uridine -- thereby directing a change in the RNA instructions. RESCUE builds on REPAIR, a technology developed by Zhang's team that changes adenine bases into inosine in RNA. RESCUE significantly expands the landscape that CRISPR tools can target RNA coding for modifiable positions in proteins, such as phosphorylation sites. Such sites act as on/off switches for protein activity and are notably found in signaling molecules and cancer-linked pathways.
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