Hypercompact adenine base editors based on transposase B guided by engineered RNA

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Title
Hypercompact adenine base editors based on transposase B guided by engineered RNA
Author(s)
D Y Kim; Y Chung; Yujin Lee; Dongmin Jeong; Kwang Hyun Park; Hyun Jung Chin; Jeong Mi Lee; S Park; S Ko; Jeong Heon KoYong-Sam Kim
Bibliographic Citation
Nature Chemical Biology, vol. 18, no. 9, pp. 1005-1013
Publication Year
2022
Abstract
Transposon-associated transposase B (TnpB) is deemed an ancestral protein for type V, Cas12 family members, and the closest ancestor to UnCas12f1. Previously, we reported a set of engineered guide RNAs supporting high indel efficiency for Cas12f1 in human cells. Here we suggest a new technology whereby the engineered guide RNAs also manifest high-efficiency programmable endonuclease activity for TnpB. We have termed this technology TaRGET (TnpB-augment RNA-based Genome Editing Technology). Having this feature in mind, we established TnpB-based adenine base editors (ABEs). A Tad-Tad mutant (V106W, D108Q) dimer fused to the C terminus of dTnpB (D354A) showed the highest levels of A-to-G conversion. The limited targetable sites for TaRGET-ABE were expanded with engineered variants of TnpB or optimized deaminases. Delivery of TaRGET-ABE also ensured potent A-to-G conversion rates in mammalian genomes. Collectively, the TaRGET-ABE will contribute to improving precise genome-editing tools that can be delivered by adeno-associated viruses, thereby harnessing the development of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene therapy.
ISSN
1552-4450
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s41589-022-01077-5
Type
Article
Appears in Collections:
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
Synthetic Biology and Bioengineering Research Institute > Genome Editing Research Center > 1. Journal Articles
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