Engineered prime editors with minimal genomic errors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40963020.
- Also identified by DOI 10.1038/s41586-025-09537-3 and PMC identifier 12571883.
- Licence recorded as CC BY-NC-ND.
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Abstract
Prime editors make programmed genome modifications by writing new sequences into extensions of nicked DNA 3' ends<sup>1</sup>. 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 errors<sup>2</sup>. 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.
Medical subject headings
- Gene Editing
- INDEL Mutation
- CRISPR-Cas Systems
- Genome
- Genomics