megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering

被引：123

作者：

Boissel, Sandrine ^{[1
,2
]}

Jarjour, Jordan ^{[3
]}

Astrakhan, Alexander ^{[3
]}

Adey, Andrew ^{[1
,4
]}

Gouble, Agnes ^{[5
]}

Duchateau, Philippe ^{[5
]}

Shendure, Jay ^{[4
]}

Stoddard, Barry L. ^{[6
]}

Certo, Michael T. ^{[2
]}

Baker, David ^{[7
,8
]}

Scharenberg, Andrew M. ^{[2
,9
]}

机构：

[1] Univ Washington, Mol & Cellular Biol Program, Seattle, WA 98195 USA

[2] Seattle Childrens Res Inst, Ctr Immun & Immunotherapies, Seattle, WA 98101 USA

[3] Pregenen Inc, Seattle, WA 98103 USA

[4] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[5] Cellectis SA, F-75013 Paris, France

[6] Fred Hutch Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA

[7] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

[8] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

[9] Univ Washington, Dept Immunol, Seattle, WA 98195 USA

来源：

NUCLEIC ACIDS RESEARCH | 2014年 / 42卷 / 04期

基金：

美国国家卫生研究院;

关键词：

DNA-BINDING SPECIFICITY; ZINC-FINGER NUCLEASES; HOMING ENDONUCLEASE; TAL EFFECTORS; BREAK REPAIR; ENZYMES;

D O I：

10.1093/nar/gkt1224

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：

Rare-cleaving endonucleases have emerged as important tools for making targeted genome modifications. While multiple platforms are now available to generate reagents for research applications, each existing platform has significant limitations in one or more of three key properties necessary for therapeutic application: efficiency of cleavage at the desired target site, specificity of cleavage (i.e. rate of cleavage at 'off-target' sites), and efficient/facile means for delivery to desired target cells. Here, we describe the development of a single-chain rare-cleaving nuclease architecture, which we designate 'megaTAL', in which the DNA binding region of a transcription activator-like (TAL) effector is used to 'address' a site-specific meganuclease adjacent to a single desired genomic target site. This architecture allows the generation of extremely active and hyper-specific compact nucleases that are compatible with all current viral and nonviral cell delivery methods.

引用

页码：2591 / 2601

页数：11

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