A study identifies La, a small RNA-binding protein, as a key enhancer of prime editing, a precise genome-editing technique. La interacts with the 3' ends of polyuridylated prime editing guide RNAs (pegRNAs), stabilizing them and improving editing efficiency. Researchers developed a modified prime editor (PE7) fused to the La protein's RNA-binding domain, which significantly enhanced prime editing across various edit types, cell types, and genomic loci. PE7 improved editing efficiency by up to 21.2-fold in U2OS cells using transiently expressed pegRNAs. La's role in prime editing is independent of mismatch repair and primarily affects the installation of intended edits. The study also shows that La's interaction with pegRNAs is crucial for their stability, and that La-accessible pegRNAs perform better with PE7. The findings suggest that La can be leveraged to optimize prime editing in primary cells and highlight the importance of pegRNA design for efficient editing. The study underscores the potential of La in enhancing prime editing efficiency and provides insights into the cellular mechanisms underlying this process.A study identifies La, a small RNA-binding protein, as a key enhancer of prime editing, a precise genome-editing technique. La interacts with the 3' ends of polyuridylated prime editing guide RNAs (pegRNAs), stabilizing them and improving editing efficiency. Researchers developed a modified prime editor (PE7) fused to the La protein's RNA-binding domain, which significantly enhanced prime editing across various edit types, cell types, and genomic loci. PE7 improved editing efficiency by up to 21.2-fold in U2OS cells using transiently expressed pegRNAs. La's role in prime editing is independent of mismatch repair and primarily affects the installation of intended edits. The study also shows that La's interaction with pegRNAs is crucial for their stability, and that La-accessible pegRNAs perform better with PE7. The findings suggest that La can be leveraged to optimize prime editing in primary cells and highlight the importance of pegRNA design for efficient editing. The study underscores the potential of La in enhancing prime editing efficiency and provides insights into the cellular mechanisms underlying this process.