Year: 2025
Type: article
Abstract: Prime editors make programmed genome modifications by writing new sequences into extensions of nicked DNA 3' ends. These edited 3' new strands must displace competing 5' strands to install edits, yet a bias toward retaining the competing 5' strands hinders efficiency and can cause indel errors. Using rational design of the constituent Cas9-nickase to reposition prime editor nicks, we discovered that competing 5' strands are destabilized to favor the edited 3' new strands. 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 465:1. One Sentence Summary: Prime editors designed with repositioned DNA breaks nearly eliminate undesired genome editing errors.
Source: Nature
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: G1734642882, G1743992157, A new high-throughput gastrointestinal tract explant platform for drug formulation discovery and metabolic disease modulation, G4774430914, G6879439366, Micro-invasive biochemical sampling of brain interstitial fluid for investigating neural pathology, Development of microRNA (miR)-based cell-targeted polymeric nanoparticles for myeloma therapy, Cancer Center Support (Core) Grant, G941982536
OpenAlex ID: W4414280301