Engineered prime editors with minimal genomic errors
Name
s41586-025-09537-3.pdf
Description
Published version
Size
8.14 MB
Format
Adobe PDF
Checksum (MD5)
0986e6161b6b92870062fc9659e30620
Author(s)
Chauhan, Vikash P
Sharp, Phillip A
Langer, Robert
Date Issued
September 17, 2025
Journal
Nature
Publisher
Springer Science and Business Media LLC
Citation
Chauhan, V.P., Sharp, P.A. & Langer, R. Engineered prime editors with minimal genomic errors. Nature (2025).
Version
Final published version
Abstract
Prime editors make programmed genome modifications by writing new sequences into extensions of nicked DNA 3′ ends1. These edited 3′ new strands must displace competing 5′ strands to install edits, yet a bias towards retaining the competing 5′ strands hinders efficiency and can cause indel errors2. Here we discover that nicked end degradation, consistent with competing 5′ strand destabilization, can be promoted by Cas9-nickase mutations that relax nick positioning. We exploit this mechanism to engineer efficient prime editors with strikingly low indel errors. Combining this error-suppressing strategy with the latest efficiency-boosting architecture, we design a next-generation prime editor (vPE). Compared with previous editors, vPE features comparable efficiency yet up to 60-fold lower indel errors, enabling edit:indel ratios as high as 543:1.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivatives
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/s41586-025-09537-3
