Commandeering an RNA-Editing Enzyme to Correct DNA Nonsense Mutations Causing Duchenne Muscular Dystrophy
Abstract
The main objective of this Idea Development Award is to lay the foundation in establishing an innovative DNA base editor that ameliorates the drawbacks and difficulties of current base-editing systems by commandeering a human RNA editing enzyme and redeploying it to serve as a DNA adenosine base editor, which would be able to correct all DMD-causing nonsense mutations. Based on our ADAR structures, we hypothesized that ADAR can deaminate adenosine in DNA, if the DNA strand is complexed with RNA, creating the requisite A-form duplex. Preliminary data does indeed show that a DNA:RNA hybrid can react with ADAR to deaminate "A" in DNA creating deoxy-inosine (dI), a guanosine analog. Then, as demonstrated in the existing base-editors, during the next cycle of DNA replication this edit would exchange an A:T base pair to G:C. Therefore, since all stop codons contain A and T bases, by editing the "A" in either the coding or non-coding strand of DNA, all nonsense mutations can be converted to a translatable codon, which would produce a full-length dystrophin protein and likely restore normal muscle function.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1219931
Entities
People
- Andrew J Fisher
Organizations
- University of California