Evaluating and Enhancing Target Specificity of Gene-Editing Nucleases and Deaminases

被引:120
作者
Kim, Daesik [1 ]
Luk, Kevin [2 ]
Wolfe, Scot A. [2 ]
Kim, Jin-Soo [1 ,3 ]
机构
[1] Inst for Basic Sci Korea, Ctr Genome Engn, Daejeon 34126, South Korea
[2] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA
[3] Seoul Natl Univ, Dept Chem, Seoul 08826, South Korea
来源
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 88 | 2019年 / 88卷
基金
美国国家卫生研究院;
关键词
CRISPR/Cas9; off-target; gene editing; base editors; Cas12a; Cpf1; GENOME-WIDE ANALYSIS; ADENOASSOCIATED VIRUS DELIVERY; ZINC-FINGER NUCLEASES; HUMAN-CELLS; CAS9; PROTEIN; CRISPR-CAS9; NUCLEASES; NEXT-GENERATION; DNA CLEAVAGE; DUAL-RNA; WEB TOOL;
D O I
10.1146/annurev-biochem-013118-111730
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Programmable nucleases and deaminases, which include zinc-finger nucleases, transcription activator-like effector nucleases, CRISPR RNA-guided nucleases, and RNA-guided base editors, are now widely employed for the targeted modification of genomes in cells and organisms. These gene-editing tools hold tremendous promise for therapeutic applications. Importantly, these nucleases and deaminases may display off-target activity through the recognition of near-cognate DNA sequences to their target sites, resulting in collateral damage to the genome in the form of local mutagenesis or genomic rearrangements. For therapeutic genome-editing applications with these classes of programmable enzymes, it is essential to measure and limit genome-wide off-target activity. Herein, we discuss the key determinants of off-target activity for these systems. We describe various cell-based and cell-free methods for identifying genome-wide off-target sites and diverse strategies that have been developed for reducing the off-target activity of programmable gene-editing enzymes.
引用
收藏
页码:191 / 220
页数:30
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