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Engineered prime editors with minimal genomic errors
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DOI：10.1038/s41586-025-09537-3.png)
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Abstract
En 中文
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. Engineered prime editor systems with reduced occurrences of unwanted insertions or deletions during genome editing are developed.
Keywords:
Prime editing
Genome editing
Indel errors
Cas9-nickase
Next-generation prime editor
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