Nuclease-directed genome editing is a powerful tool for investigating physiology and has great promise as a therapeutic approach to correct mutations that cause disease. In its most precise form, genome editing can use cellular homology-directed repair (HDR) pathways to insert information from an exogenously supplied DNA repair template (donor) directly into a targeted genomic location. Unfortunately, particularly for long insertions, toxicity and delivery considerations associated with repair template DNA can limit HDR efficacy. Here, we explore chemical modifications to both double-stranded and single-stranded DNA-repair templates. We describe 5′-terminal modifications, including in its simplest form the incorporation of triethylene glycol (TEG) moieties, that consistently increase the frequency of precision editing in the germlines of three animal models (Caenorhabditis elegans, zebrafish, mice) and in human cell cultures.

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5'修饰提高了DNA供体用于精确基因组编辑的效力和功效

核酸酶指导的基因组编辑是研究生理学的有力工具，作为纠正导致疾病的突变的治疗方法具有广阔的前景。以最精确的形式，基因组编辑可以使用细胞同源性指导的修复（HDR）途径，将来自外源提供的DNA修复模板（供体）的信息直接插入目标基因组位置。不幸的是，特别是对于长插入而言，与修复模板DNA相关的毒性和递送考虑因素可能会限制HDR功效。在这里，我们探索对双链和单链DNA修复模板的化学修饰。我们描述了5'-末端修饰，包括以最简单的形式引入三甘醇（TEG）部分，