1932

Abstract

Current technology enables the production of highly specific genome modifications with excellent efficiency and specificity. Key to this capability are targetable DNA cleavage reagents and cellular DNA repair pathways. The break made by these reagents can produce localized sequence changes through inaccurate nonhomologous end joining (NHEJ), often leading to gene inactivation. Alternatively, user-provided DNA can be used as a template for repair by homologous recombination (HR), leading to the introduction of desired sequence changes. This review describes three classes of targetable cleavage reagents: zinc-finger nucleases (ZFNs), transcription activator–like effector nucleases (TALENs), and CRISPR/Cas RNA-guided nucleases (RGNs). As a group, these reagents have been successfully used to modify genomic sequences in a wide variety of cells and organisms, including humans. This review discusses the properties, advantages, and limitations of each system, as well as the specific considerations required for their use in different biological systems.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-060713-035418
2014-06-02
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/biochem/83/1/annurev-biochem-060713-035418.html?itemId=/content/journals/10.1146/annurev-biochem-060713-035418&mimeType=html&fmt=ahah

Literature Cited

  1. Smithies O, Gregg RG, Boggs SS, Koralewski MA, Kucherlapati RS. 1.  1985. Insertion of DNA sequences into the human chromosomal β-globin locus by homologous recombination. Nature 317:230–34 [Google Scholar]
  2. Thomas KR, Folger KR, Capecchi MR. 2.  1986. High frequency targeting of genes to specific sites in the mammalian genome. Cell 44:419–28 [Google Scholar]
  3. Mansour SL, Thomas KR, Capecchi MR. 3.  1988. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature 336:348–52 [Google Scholar]
  4. Rothstein RJ.4.  1983. One-step gene disruption in yeast. Methods Enzymol. 101:202–11 [Google Scholar]
  5. Scherer S, Davis RW. 5.  1979. Replacement of chromosome segments with altered DNA sequences constructed in vitro. Proc. Natl. Acad. Sci. USA 76:4951–55 [Google Scholar]
  6. Rong YS, Golic KG. 6.  2000. Gene targeting by homologous recombination in Drosophila. Science 288:2013–18 [Google Scholar]
  7. Latt SA.7.  1981. Sister chromatid exchange formation. Annu. Rev. Genet. 15:11–53 [Google Scholar]
  8. Youds JL, Boulton SJ. 8.  2011. The choice in meiosis—defining the factors that influence crossover or non-crossover formation. J. Cell Sci. 124:501–13 [Google Scholar]
  9. Haber JE.9.  2012. Mating-type genes and MAT switching in Saccharomyces cerevisiae. Genetics 191:33–64 [Google Scholar]
  10. Choulika A, Perrin A, Dujon B, Nicolas J-F. 10.  1995. Induction of homologous recombination in mammalian chromosomes by using the I-SceI system of Saccharomyces cerevisiae. Mol. Cell. Biol. 15:1968–73 [Google Scholar]
  11. Plessis A, Perrin A, Haber JE, Dujon B. 11.  1992. Site-specific recombination determined by I-SceI, a mitochondrial group I intron–encoded endonuclease expressed in the yeast nucleus. Genetics 130:451–60 [Google Scholar]
  12. Rouet P, Smih F, Jasin M. 12.  1994. Introduction of double-strand breaks into the genome of mouse cells by expression of a rare-cutting endonuclease. Mol. Cell. Biol. 14:8096–106 [Google Scholar]
  13. Rudin N, Sugarman E, Haber JE. 13.  1989. Genetic and physical analysis of double-strand break repair and recombination in Saccharomyces cerevisiae. Genetics 122:519–34 [Google Scholar]
  14. Chapman JR, Taylor MR, Boulton SJ. 14.  2012. Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell 47:497–510 [Google Scholar]
  15. Chin JY, Glazer PM. 15.  2009. Repair of DNA lesions associated with triplex-forming oligonucleotides. Mol. Carcinog. 48:389–99 [Google Scholar]
  16. Doss RM, Marques MA, Foister S, Chenoweth DM, Dervan PB. 16.  2006. Programmable oligomers for minor groove DNA recognition. J. Am. Chem. Soc. 128:9074–79 [Google Scholar]
  17. Kim KH, Nielsen PE, Glazer PM. 17.  2006. Site-specific gene modification by PNAs conjugated to psoralen. Biochemistry 45:314–23 [Google Scholar]
  18. Carroll D.18.  2011. Genome engineering with zinc-finger nucleases. Genetics 188:773–82 [Google Scholar]
  19. Kim Y-G, Cha J, Chandrasegaran S. 19.  1996. Hybrid restriction enzymes: zinc finger fusions to FokI cleavage domain. Proc. Natl. Acad. Sci. USA 93:1156–60 [Google Scholar]
  20. Joung JK, Sander JD. 20.  2013. TALENs: a widely applicable technology for targeted genome editing. Nat. Rev. Mol. Cell Biol. 14:49–55 [Google Scholar]
  21. Carroll D.21.  2012. A CRISPR approach to gene targeting. Mol. Ther. 20:1658–60 [Google Scholar]
  22. Gaj T, Gersbach CA, Barbas CF 3rd. 22.  2013. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 31:397–405 [Google Scholar]
  23. Barzel A, Privman E, Peeri M, Naor A, Shachar E. 23.  et al. 2011. Native homing endonucleases can target conserved genes in humans and in animal models. Nucleic Acids Res. 39:6646–59 [Google Scholar]
  24. Takeuchi R, Lambert AR, Mak AN, Jacoby K, Dickson RJ. 24.  et al. 2011. Tapping natural reservoirs of homing endonucleases for targeted gene modification. Proc. Natl. Acad. Sci. USA 108:13077–82 [Google Scholar]
  25. Stoddard BL.25.  2011. Homing endonucleases: from microbial genetic invaders to reagents for targeted DNA modifications. Structure 19:7–15 [Google Scholar]
  26. Li L, Wu LP, Chandrasegaran S. 26.  1992. Functional domains in FokI restriction endonuclease. Proc. Natl. Acad. Sci. USA 89:4275–79 [Google Scholar]
  27. Kim Y-G, Chandrasegaran S. 27.  1994. Chimeric restriction endonuclease. Proc. Natl. Acad. Sci. USA 91:883–87 [Google Scholar]
  28. Miller J, McLachlan AD, Klug A. 28.  1985. Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes. EMBO J. 4:1609–14 [Google Scholar]
  29. Berg JM.29.  1988. Proposed structure for the zinc-binding domains from transcription factor IIIA and related proteins. Proc. Natl. Acad. Sci. USA 85:99–102 [Google Scholar]
  30. Pavletich NP, Pabo CO. 30.  1991. Zinc finger–DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 Å resolution. Science 252:809–17 [Google Scholar]
  31. Pabo CO, Peisach E, Grant RA. 31.  2001. Design and selection of novel Cys2His2 zinc finger proteins. Annu. Rev. Biochem. 70:313–40 [Google Scholar]
  32. Desjarlais JR, Berg JM. 32.  1992. Toward rules relating zinc finger protein sequences and DNA binding site preferences. Proc. Natl. Acad. Sci. USA 89:7345–49 [Google Scholar]
  33. Desjarlais JR, Berg JM. 33.  1993. Use of a zinc-finger consensus sequence framework and specificity rules to design specific DNA binding proteins. Proc. Natl. Acad. Sci. USA 90:2256–60 [Google Scholar]
  34. Choo Y, Klug A. 34.  1994. Toward a code for the interactions of zinc fingers with DNA: selection of randomized fingers displayed on phage. Proc. Natl. Acad. Sci. USA 91:11163–67 [Google Scholar]
  35. Choo Y, Klug A. 35.  1994. Selection of DNA binding sites for zinc fingers using rationally randomized DNA reveals coded interactions. Proc. Natl. Acad. Sci. USA 91:11168–72 [Google Scholar]
  36. Greisman HA, Pabo CO. 36.  1997. A general strategy for selecting high-affinity zinc finger proteins for diverse DNA target sites. Science 275:657–61 [Google Scholar]
  37. Segal DJ, Dreier B, Beerli RR, Barbas CF 3rd. 37.  1999. Toward controlling gene expression at will: selection and design of zinc finger domains recognizing each of the 5′-GNN-3′ DNA target sequences. Proc. Natl. Acad. Sci. USA 96:2758–63 [Google Scholar]
  38. Dreier B, Beerli RR, Segal DJ, Flippin JD, Barbas CF 3rd. 38.  2001. Development of zinc finger domains for recognition of the 5′-ANN-3′ family of DNA sequences and their use in the construction of artificial transcription factors. J. Biol. Chem. 276:29466–78 [Google Scholar]
  39. Dreier B, Fuller RP, Segal DJ, Lund C, Blancafort P. 39.  et al. 2005. Development of zinc finger domains for recognition of the 5′-CNN-3′ family DNA sequences and their use in construction of artificial transcription factors. J. Biol. Chem. 280:35588–97 [Google Scholar]
  40. Liu Q, Xia ZQ, Zhong X, Case CC. 40.  2002. Validated zinc finger protein designs for all 16 GNN DNA triplet targets. J. Biol. Chem. 277:3850–56 [Google Scholar]
  41. Kim HJ, Lee HJ, Kim H, Cho SW, Kim JS. 41.  2009. Targeted genome editing in human cells with zinc finger nucleases constructed via modular assembly. Genome Res. 19:1279–88 [Google Scholar]
  42. Bhakta MS, Henry IM, Ousterout DG, Das KT, Lockwood SH. 42.  et al. 2013. Highly active zinc-finger nucleases by extended modular assembly. Genome Res. 23:530–38 [Google Scholar]
  43. Carroll D, Morton JJ, Beumer KJ, Segal DJ. 43.  2006. Design, construction and in vitro testing of zinc finger nucleases. Nat. Protoc. 1:1329–41 [Google Scholar]
  44. Gonzalez B, Schwimmer LJ, Fuller RP, Ye Y, Asawapornmongkol L, Barbas CF 3rd. 44.  2010. Modular system for the construction of zinc-finger libraries and proteins. Nat. Protoc. 5:791–810 [Google Scholar]
  45. Kim JS, Lee HJ, Carroll D. 45.  2010. Genome editing with modularly assembled zinc-finger nucleases. Nat. Methods 7:91 [Google Scholar]
  46. Segal DJ, Beerli RR, Blancafort P, Dreier B, Effertz K. 46.  et al. 2003. Evaluation of a modular strategy for the construction of novel polydactyl zinc finger DNA-binding proteins. Biochemistry 42:2137–48 [Google Scholar]
  47. Ramirez CL, Foley JE, Wright DA, Müller-Lerch F, Rahman SH. 47.  et al. 2008. Unexpected failure rates for modular assembly of engineered zinc fingers. Nat. Methods 5:374–75 [Google Scholar]
  48. Meng X, Thibodeau-Beganny S, Jiang T, Joung JK, Wolfe SA. 48.  2007. Profiling the DNA-binding specificities of engineered Cys2His2 zinc finger domains using a rapid cell-based method. Nucleic Acids Res. 35:e81 [Google Scholar]
  49. Maeder ML, Thibodeau-Beganny S, Osiak A, Wright DA, Anthony RM. 49.  et al. 2008. Rapid “open-source” engineering of customized zinc-finger nucleases for highly efficient gene modification. Mol. Cell 31:294–301 [Google Scholar]
  50. Gupta A, Christensen RG, Rayla AL, Lakshmanan A, Stormo GD, Wolfe SA. 50.  2012. An optimized two-finger archive for ZFN-mediated gene targeting. Nat. Methods 9:588–90 [Google Scholar]
  51. Sander JD, Dahlborg EJ, Goodwin MJ, Cade L, Zhang F. 51.  et al. 2011. Selection-free zinc-finger-nuclease engineering by context-dependent assembly (CoDA). Nat. Methods 8:67–69 [Google Scholar]
  52. Zhu C, Gupta A, Hall VL, Rayla AL, Christensen RG. 52.  et al. 2013. Using defined finger-finger interfaces as units of assembly for constructing zinc-finger nucleases. Nucleic Acids Res. 41:2455–65 [Google Scholar]
  53. Shimizu Y, Şöllü C, Meckler JF, Adriaenssens A, Zykovich A. 53.  et al. 2011. Adding fingers to an engineered zinc finger nuclease can reduce activity. Biochemistry 50:5033–41 [Google Scholar]
  54. Moore M, Klug A, Choo Y. 54.  2001. Improved DNA binding specificity from polyzinc finger peptides by using strings of two-finger units. Proc. Natl. Acad. Sci. USA 98:1437–41 [Google Scholar]
  55. Moore M, Choo Y, Klug A. 55.  2001. Design of polyzinc finger peptides with structured linkers. Proc. Natl. Acad. Sci. USA 98:1432–36 [Google Scholar]
  56. Krizek BA, Amann BT, Kilfoil VJ, Merkle DL, Berg JM. 56.  1991. A consensus zinc finger peptide: design, high-affinity metal binding, a pH-dependent structure, and a His to Cys sequence variant. J. Am. Chem. Soc. 113:4518–23 [Google Scholar]
  57. Smith J, Bibikova M, Whitby FG, Reddy AR, Chandrasegaran S, Carroll D. 57.  2000. Requirements for double-strand cleavage by chimeric restriction enzymes with zinc finger DNA-recognition domains. Nucleic Acids Res. 28:3361–69 [Google Scholar]
  58. Bitinaite J, Wah DA, Aggarwal AK, Schildkraut I. 58.  1998. FokI dimerization is required for DNA cleavage. Proc. Natl. Acad. Sci. USA 95:10570–75 [Google Scholar]
  59. Guo J, Gaj T, Barbas CF 3rd. 59.  2010. Directed evolution of an enhanced and highly efficient FokI cleavage domain for zinc finger nucleases. J. Mol. Biol. 400:96–107 [Google Scholar]
  60. Bibikova M, Carroll D, Segal DJ, Trautman JK, Smith J. 60.  et al. 2001. Stimulation of homologous recombination through targeted cleavage by chimeric nucleases. Mol. Cell. Biol. 21:289–97 [Google Scholar]
  61. Handel EM, Alwin S, Cathomen T. 61.  2009. Expanding or restricting the target site repertoire of zinc-finger nucleases: the inter-domain linker as a major determinant of target site selectivity. Mol. Ther. 17:104–11 [Google Scholar]
  62. Shimizu Y, Bhakta MS, Segal DJ. 62.  2009. Restricted spacer tolerance of a zinc finger nuclease with a six amino acid linker. Bioorg. Med. Chem. Lett. 19:3970–72 [Google Scholar]
  63. Urnov FD, Miller JC, Lee Y-L, Beausejour CM, Rock JM. 63.  et al. 2005. Highly efficient endogenous gene correction using designed zinc-finger nucleases. Nature 435:646–51 [Google Scholar]
  64. Bogdanove AJ, Voytas DF. 64.  2011. TAL effectors: customizable proteins for DNA targeting. Science 333:1843–46 [Google Scholar]
  65. Boch J, Scholze H, Schornack S, Landgraf A, Hahn S. 65.  et al. 2009. Breaking the code of DNA binding specificity of TAL-type III effectors. Science 326:1509–12 [Google Scholar]
  66. Moscou MJ, Bogdanove AJ. 66.  2009. A simple cipher governs DNA recognition by TAL effectors. Science 326:1501 [Google Scholar]
  67. Deng D, Yan C, Pan X, Mahfouz M, Wang J. 67.  et al. 2012. Structural basis for sequence-specific recognition of DNA by TAL effectors. Science 335:720–23 [Google Scholar]
  68. Mak AN-S, Bradley P, Cernadas RA, Bogdanove AJ, Stoddard BL. 68.  2012. The crystal structure of TAL effector PthXo1 bound to its DNA target. Science 335:716–19 [Google Scholar]
  69. Christian ML, Demorest ZL, Starker CG, Osborn MJ, Nyquist MD. 69.  et al. 2012. Targeting G with TAL effectors: a comparison of activities of TALENs constructed with NN and NK repeat variable di-residues. PLoS ONE 7:e45383 [Google Scholar]
  70. Cong L, Zhou R, Kuo YC, Cunniff M, Zhang F. 70.  2012. Comprehensive interrogation of natural TALE DNA-binding modules and transcriptional repressor domains. Nat. Commun. 3:968 [Google Scholar]
  71. Streubel J, Blucher C, Landgraf A, Boch J. 71.  2012. TAL effector RVD specificities and efficiencies. Nat. Biotechnol. 30:593–95 [Google Scholar]
  72. Meckler JF, Bhakta MS, Kim MS, Ovadia R, Habrian CH. 72.  et al. 2013. Quantitative analysis of TALE-DNA interactions suggests polarity effects. Nucleic Acids Res. 41:4118–28 [Google Scholar]
  73. Valton J, Dupuy A, Daboussi F, Thomas S, Marechal A. 73.  et al. 2012. Overcoming transcription activator–like effector (TALE) DNA binding domain sensitivity to cytosine methylation. J. Biol. Chem. 287:38427–32 [Google Scholar]
  74. Briggs AW, Rios X, Chari R, Yang L, Zhang F. 74.  et al. 2012. Iterative capped assembly: rapid and scalable synthesis of repeat-module DNA such as TAL effectors from individual monomers. Nucleic Acids Res. 40:e117 [Google Scholar]
  75. Cermak T, Doyle EL, Christian M, Wang L, Zhang Y. 75.  et al. 2011. Efficient design and assembly of custom TALEN and other TAL effector–based constructs for DNA targeting. Nucleic Acids Res. 39:e82 [Google Scholar]
  76. Huang P, Xiao A, Zhou M, Zhu Z, Lin S, Zhang B. 76.  2011. Heritable gene targeting in zebrafish using customized TALENs. Nat. Biotechnol. 29:699–700 [Google Scholar]
  77. Morbitzer R, Elsässer J, Hausner J, Lahaye T. 77.  2011. Assembly of custom TALE-type DNA binding domains by modular cloning. Nucleic Acids Res. 39:5790–99 [Google Scholar]
  78. Neff KL, Argue DP, Ma AC, Lee HB, Clark KJ, Ekker SC. 78.  2013. Mojo Hand, a TALEN design tool for genome editing applications. BMC Bioinforma. 14:1 [Google Scholar]
  79. Reyon D, Khayter C, Regan MR, Joung JK, Sander JD. 79.  2012. Engineering designer transcription activator–like effector nucleases (TALENs) by REAL or REAL-Fast assembly. Curr. Protoc. Mol. Biol. 12:12.15 [Google Scholar]
  80. Reyon D, Tsai SQ, Khayter C, Foden JA, Sander JD, Joung JK. 80.  2012. FLASH assembly of TALENs for high-throughput genome editing. Nat. Biotechnol. 30:460–65 [Google Scholar]
  81. Sakuma T, Hosoi S, Woltjen K, Suzuki K, Kashiwagi K. 81.  et al. 2013. Efficient TALEN construction and evaluation methods for human cell and animal applications. Genes Cells 18:315–26 [Google Scholar]
  82. Sanjana NE, Cong L, Zhou Y, Cunniff MM, Feng G, Zhang F. 82.  2012. A transcription activator–like effector toolbox for genome engineering. Nat. Protoc. 7:171–92 [Google Scholar]
  83. Schmid-Burgk JL, Schmidt T, Kaiser V, Honing K, Hornung V. 83.  2013. A ligation-independent cloning technique for high-throughput assembly of transcription activator–like effector genes. Nat. Biotechnol. 31:76–81 [Google Scholar]
  84. Uhde-Stone C, Gor N, Chin T, Huang J, Lu B. 84.  2013. A do-it-yourself protocol for simple transcription activator–like effector assembly. Biol. Proced. Online 15:3 [Google Scholar]
  85. Wang Z, Li J, Huang H, Wang G, Jiang M. 85.  et al. 2012. An integrated chip for the high-throughput synthesis of transcription activator–like effectors. Angew. Chem. Int. Ed. Engl. 51:8505–8 [Google Scholar]
  86. Weber E, Gruetzner R, Werner S, Engler C, Marillonnet S. 86.  2011. Assembly of designer TAL effectors by Golden Gate cloning. PLoS ONE 6:e19722 [Google Scholar]
  87. Christian M, Cermak T, Doyle EL, Schmidt C, Zhang F. 87.  et al. 2010. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186:757–61 [Google Scholar]
  88. Li T, Huang S, Jiang WZ, Wright D, Spalding MH. 88.  et al. 2011. TAL nucleases (TALNs): hybrid proteins composed of TAL effectors and FokI DNA-cleavage domain. Nucleic Acids Res. 39:359–72 [Google Scholar]
  89. Miller JC, Tan S, Qiao G, Barlow KA, Wang J. 89.  et al. 2011. A TALE nuclease architecture for efficient genome editing. Nat. Biotechnol. 29:143–48 [Google Scholar]
  90. Sorek R, Lawrence CM, Wiedenheft B. 90.  2013. CRISPR-mediated adaptive immune systems in bacteria and archaea. Annu. Rev. Biochem. 82:237–66 [Google Scholar]
  91. Jansen R, Embden JD, Gaastra W, Schouls LM. 91.  2002. Identification of genes that are associated with DNA repeats in prokaryotes. Mol. Microbiol. 43:1565–75 [Google Scholar]
  92. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna J, Charpentier E. 92.  2012. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–21 [Google Scholar]
  93. Cho SW, Kim S, Kim JM, Kim J-S. 93.  2013. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat. Biotechnol. 31:230–32 [Google Scholar]
  94. Cong L, Ran FA, Cox D, Lin S, Barretto R. 94.  et al. 2013. Mutliplex genome engineering using CRISPR/Cas systems. Science 339:819–23 [Google Scholar]
  95. Jinek M, East A, Cheng A, Lin S, Ma E, Doudna J. 95.  2013. RNA-programmed genome editing in human cells. eLife 2:e00471 [Google Scholar]
  96. Mali P, Yang L, Esvelt KM, Aach J, Guell M. 96.  et al. 2013. RNA-guided human genome engineering via Cas9. Science 339:823–26 [Google Scholar]
  97. Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai SQ. 97.  et al. 2013. Efficient genome editing in zebrafish using a CRISPR–Cas system. Nat. Biotechnol. 31:227–29 [Google Scholar]
  98. Hsu PD, Scott DA, Weinstein JA, Ran FA, Konermann S. 98.  et al. 2013. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat. Biotechnol. 31:827–32 [Google Scholar]
  99. Mali P, Aach J, Stranges PB, Esvelt KM, Moosburner M. 99.  et al. 2013. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat. Biotechnol. 31:833–38 [Google Scholar]
  100. Fu Y, Sander JD, Reyon D, Cascio VM, Joung JK. 100.  2014. Improving CRISPR–Cas nuclease specificity using truncated guide RNAs. Nat. Biotechnol. 32279–84
  101. Cho SW, Kim S, Kim Y, Kweon J, Kim HS. 101.  et al. 2013. Analysis of off-target effects of CRISPR/Cas-derived RNA-guided endonucleases and nickases. Genome Res. 24:132–41 [Google Scholar]
  102. Jinek M, Jiang F, Taylor DW, Sternberg SH, Kaya E. 102.  et al. 2014. Structures of Cas9 endonucleases reveal RNA-mediated conformational activation. Science. In press
  103. Nishimasu H, Ran FA, Hsu PD, Konermann S, Shehata SI. 103.  et al. 2014. Crystal structure of Cas9 in complex with guide RNA and target DNA. Cell 156935–49
  104. Beurdeley M, Bietz F, Li J, Thomas S, Stoddard T. 104.  et al. 2013. Compact designer TALENs for efficient genome engineering. Nat. Commun. 4:1762 [Google Scholar]
  105. Kleinstiver BP, Wolfs JM, Kolaczyk T, Roberts AK, Hu SX, Edgell DR. 105.  2012. Monomeric site-specific nucleases for genome editing. Proc. Natl. Acad. Sci. USA 109:8061–66 [Google Scholar]
  106. Schierling B, Dannemann N, Gabsalilow L, Wende W, Cathomen T, Pingoud A. 106.  2012. A novel zinc-finger nuclease platform with a sequence-specific cleavage module. Nucleic Acids Res. 40:2623–38 [Google Scholar]
  107. Gabsalilow L, Schierling B, Friedhoff P, Pingoud A, Wende W. 107.  2013. Site- and strand-specific nicking of DNA by fusion proteins derived from MutH and I-SceI or TALE repeats. Nucleic Acids Res. 41:e83 [Google Scholar]
  108. Blancafort P, Segal DJ, Barbas CF 3rd. 108.  2004. Designing transcription factor architectures for drug discovery. Mol. Pharmacol. 66:1361–71 [Google Scholar]
  109. Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA. 109.  et al. 2013. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154:442–51 [Google Scholar]
  110. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS. 110.  et al. 2013. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152:1173–83 [Google Scholar]
  111. Gaj T, Mercer AC, Sirk SJ, Smith HL, Barbas CF 3rd. 111.  2013. A comprehensive approach to zinc-finger recombinase customization enables genomic targeting in human cells. Nucleic Acids Res. 41:3937–46 [Google Scholar]
  112. Mercer AC, Gaj T, Fuller RP, Barbas CF 3rd. 112.  2012. Chimeric TALE recombinases with programmable DNA sequence specificity. Nucleic Acids Res. 40:11163–72 [Google Scholar]
  113. Bibikova M, Golic M, Golic KG, Carroll D. 113.  2002. Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics 161:1169–75 [Google Scholar]
  114. Gong WJ, Golic KG. 114.  2003. Ends-out, or replacement, gene targeting in Drosophila. Proc. Natl. Acad. Sci. USA 100:2556–61 [Google Scholar]
  115. Bibikova M, Beumer K, Trautman JK, Carroll D. 115.  2003. Enhancing gene targeting with designed zinc finger nucleases. Science 300:764 [Google Scholar]
  116. Porteus MH, Baltimore D. 116.  2003. Chimeric nucleases stimulate gene targeting in human cells. Science 300:763 [Google Scholar]
  117. Gaj T, Guo J, Kato Y, Sirk SJ, Barbas CF 3rd. 117.  2012. Targeted gene knockout by direct delivery of zinc-finger nuclease proteins. Nat. Methods 9:805–7 [Google Scholar]
  118. Doyon Y, McCammon JM, Miller JC, Faraji F, Ngo C. 118.  et al. 2008. Heritable targeted gene disruption in zebrafish using designed zinc-finger nucleases. Nat. Biotechnol. 26:702–8 [Google Scholar]
  119. Meng X, Noyes MB, Zhu LJ, Lawson ND, Wolfe SA. 119.  2008. Targeted gene inactivation in zebrafish using engineered zinc-finger nucleases. Nat. Biotechnol. 26:695–701 [Google Scholar]
  120. Carbery ID, Ji D, Harrington A, Brown V, Weinstein EJ. 120.  et al. 2010. Targeted genome modification in mice using zinc-finger nucleases. Genetics 186:451–59 [Google Scholar]
  121. Carlson DF, Tan W, Lillico SG, Stverakova D, Proudfoot C. 121.  et al. 2012. Efficient TALEN-mediated gene knockout in livestock. Proc. Natl. Acad. Sci. USA 109:17382–87 [Google Scholar]
  122. Cui X, Ji D, Fisher DA, Wu Y, Briner DM, Weinstein EJ. 122.  2011. Targeted integration in rat and mouse embryos with zinc-finger nucleases. Nat. Biotechnol. 29:64–67 [Google Scholar]
  123. Geurts AM, Cost GJ, Freyvert Y, Zeitler B, Miller JC. 123.  et al. 2009. Knockout rats via embryo microinjection of zinc-finger nucleases. Science 325:433 [Google Scholar]
  124. Hauschild J, Petersen B, Santiago Y, Queisser AL, Carnwath JW. 124.  et al. 2011. Efficient generation of a biallelic knockout in pigs using zinc-finger nucleases. Proc. Natl. Acad. Sci. USA 108:12013–17 [Google Scholar]
  125. Meyer M, Hrabé de Angelis M, Wurst W, Kühn R. 125.  2010. Gene targeting by homologous recombination in mouse zygotes mediated by zinc-finger nucleases. Proc. Natl. Acad. Sci. USA 107:15022–26 [Google Scholar]
  126. Beumer KJ, Trautman JK, Bozas A, Liu J-L, Rutter J. 126.  et al. 2008. Efficient gene targeting in Drosophila by direct embryo injection with zinc-finger nucleases. Proc. Natl. Acad. Sci. USA 105:19821–26 [Google Scholar]
  127. Bedell VM, Wang Y, Campbell JM, Poshusta TL, Starker CG. 127.  et al. 2012. In vivo genome editing using a high-efficiency TALEN system. Nature 491:114–18 [Google Scholar]
  128. Hwang WY, Fu Y, Reyon D, Maeder ML, Kaini P. 128.  et al. 2013. Heritable and precise zebrafish genome editing using a CRISPR–Cas system. PLoS ONE 8:e68708 [Google Scholar]
  129. Zu Y, Tong X, Wang Z, Liu D, Pan R. 129.  et al. 2013. TALEN-mediated precise genome modification by homologous recombination in zebrafish. Nat. Methods 10:329–31 [Google Scholar]
  130. Morton J, Davis MW, Jorgensen EM, Carroll D. 130.  2006. Induction and repair of zinc-finger nuclease–targeted double-strand breaks in Caenorhabditis elegans somatic cells. Proc. Natl. Acad. Sci. USA 103:16370–75 [Google Scholar]
  131. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. 131.  1998. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–11 [Google Scholar]
  132. Friedland AE, Tzur YB, Esvelt KM, Colaiacovo MP, Church GM, Calarco JA. 132.  2013. Heritable genome editing in C. elegans via a CRISPR–Cas9 system. Nat. Methods 10:741–43 [Google Scholar]
  133. Lo TW, Pickle CS, Lin S, Ralston EJ, Gurling M. 133.  et al. 2013. Heritable genome editing using TALENs and CRISPR/Cas9 to engineer precise insertions and deletions in evolutionarily diverse nematode species. Genetics 195:331–48 [Google Scholar]
  134. Wood AJ, Lo TW, Zeitler B, Pickle CS, Ralston EJ. 134.  et al. 2011. Targeted genome editing across species using ZFNs and TALENs. Science 333:307 [Google Scholar]
  135. Chen S, Oikonomou G, Chiu CN, Niles BJ, Liu J. 135.  et al. 2013. A large-scale in vivo analysis reveals that TALENs are significantly more mutagenic than ZFNs generated using context-dependent assembly. Nucleic Acids Res. 41:2769–78 [Google Scholar]
  136. Chiu H, Schwartz HT, Antoshechkin I, Sternberg PW. 136.  2013. Transgene-free genome editing in Caenorhabditis elegans using CRISPR–Cas. Genetics 195:1167–71 [Google Scholar]
  137. Dickinson DJ, Ward JD, Reiner DJ, Goldstein B. 137.  2013. Engineering the Caenorhabditis elegans genome using Cas9-triggered homologous recombination. Nat. Methods 10:1028–34 [Google Scholar]
  138. Katic I, Grosshans H. 138.  2013. Targeted heritable mutation and gene conversion by Cas9-CRISPR in Caenorhabditis elegans. Genetics 195:1173–76 [Google Scholar]
  139. Tzur YB, Friedland AE, Nadarajan S, Church GM, Calarco JA, Colaiacovo MP. 139.  2013. Heritable custom genomic modifications in Caenorhabditis elegans via a CRISPR–Cas9 system. Genetics 195:1181–85 [Google Scholar]
  140. Waaijers S, Portegijs V, Kerver J, Lemmens BB, Tijsterman M. 140.  et al. 2013. CRISPR/Cas9-targeted mutagenesis in Caenorhabditis elegans. Genetics 195:1187–91 [Google Scholar]
  141. Cho SW, Lee J, Carroll D, Kim JS, Lee J. 141.  2013. Heritable gene knockout in Caenorhabditis elegans by direct injection of Cas9-sgRNA ribonucleoproteins. Genetics 195:1177–80 [Google Scholar]
  142. Miller JC, Holmes MC, Wang J, Guschin DY, Lee Y-L. 142.  et al. 2007. An improved zinc-finger nuclease architecture for highly specific genome cleavage. Nat. Biotechnol. 25:778–85 [Google Scholar]
  143. Qiu P, Shandilya H, D'Alessio JM, O'Connor K, Durocher J, Gerard GF. 143.  2004. Mutation detection using Surveyor nuclease. Biotechniques 36:702–7 [Google Scholar]
  144. Dahlem TJ, Hoshijima K, Jurynec MJ, Gunther D, Starker CG. 144.  et al. 2012. Simple methods for generating and detecting locus-specific mutations induced with TALENs in the zebrafish genome. PLoS Genet. 8:e1002861 [Google Scholar]
  145. Beumer KJ, Trautman JK, Christian M, Dahlem TJ, Lake CM. 145.  et al. 2013. Comparing ZFNs and TALENs for gene targeting in Drosophila. G3 3:1717–25 [Google Scholar]
  146. Kim Y-G, Kweon J, Kim J-S. 146.  2013. TALENs and ZFNs are associated with different mutation signatures. Nat. Methods 10:185 [Google Scholar]
  147. Delacôte F, Perez C, Guyot V, Duhamel M, Rochon C. 147.  et al. 2013. High frequency targeted mutagenesis using engineered endonucleases and DNA-end processing enzymes. PLoS ONE 8:e53217 [Google Scholar]
  148. Mashimo T, Kaneko T, Sakuma T, Kobayashi J, Kunihiro Y. 148.  et al. 2013. Efficient gene targeting by TAL effector nucleases coinjected with exonucleases in zygotes. Sci. Rep. 3:1253 [Google Scholar]
  149. Yu AM, McVey M. 149.  2010. Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions. Nucleic Acids Res. 38:5706–17 [Google Scholar]
  150. Bozas A, Beumer KJ, Trautman JK, Carroll D. 150.  2009. Genetic analysis of zinc-finger nuclease-induced gene targeting in Drosophila. Genetics 182:641–51 [Google Scholar]
  151. Lee HJ, Kim E, Kim JS. 151.  2010. Targeted chromosomal deletions in human cells using zinc finger nucleases. Genome Res. 20:81–89 [Google Scholar]
  152. Gupta A, Hall VL, Kok FO, Shin M, McNulty JC. 152.  et al. 2013. Targeted chromosomal deletions and inversions in zebrafish. Genome Res. 23:1008–17 [Google Scholar]
  153. Lee HJ, Kweon J, Kim E, Kim S, Kim JS. 153.  2012. Targeted chromosomal duplications and inversions in the human genome using zinc finger nucleases. Genome Res. 22:539–48 [Google Scholar]
  154. Brunet E, Simsek D, Tomishima M, DeKelver RC, Choi VM. 154.  et al. 2009. Chromosomal translocations induced as specified loci in human stem cells. Proc. Natl. Acad. Sci. USA 106:10620–25 [Google Scholar]
  155. Piganeau M, Ghezraoui H, De Cian A, Guittat L, Tomishima M. 155.  et al. 2013. Cancer translocations in human cells induced by zinc finger and TALE nucleases. Genome Res. 23:1182–93 [Google Scholar]
  156. Chen F, Pruett-Miller SM, Huang Y, Gjoka M, Duda K. 156.  et al. 2011. High-frequency genome editing using ssDNA oligonucleotides with zinc-finger nucleases. Nat. Methods 8:753–55 [Google Scholar]
  157. Kim E, Kim S, Kim DH, Choi BS, Choi IY, Kim J-S. 157.  2012. Precision genome engineering with programmable DNA-nicking enzymes. Genome Res. 22:1327–33 [Google Scholar]
  158. McConnell Smith A, Takeuchi R, Pellenz S, Davis L, Maizels N. 158.  et al. 2009. Generation of a nicking enzyme that stimulates site-specific gene conversion from the I-AniI LAGLIDADG homing endonuclease. Proc. Natl. Acad. Sci. USA 106:5099–104 [Google Scholar]
  159. Ramirez CL, Certo MT, Mussolino C, Goodwin MJ, Cradick TJ. 159.  et al. 2012. Engineered zinc finger nickases induce homology-directed repair with reduced mutagenic effects. Nucleic Acids Res. 40:5560–68 [Google Scholar]
  160. Wang J, Friedman G, Doyon Y, Wang NS, Li CJ. 160.  et al. 2012. Targeted gene addition to a predetermined site in the human genome using a ZFN-based nicking enzyme. Genome Res. 22:1316–26 [Google Scholar]
  161. Certo MT, Ryu BY, Annis JE, Garibov M, Jarjour J. 161.  et al. 2011. Tracking genome engineering outcome at individual DNA breakpoints. Nat. Methods 8:671–76 [Google Scholar]
  162. Beumer KJ, Trautman JK, Mukherjee K, Carroll D. 162.  2013. Donor DNA utilization during gene targeting with zinc-finger nucleases. G3 3:657–64 [Google Scholar]
  163. Elliott B, Richardson C, Winderbaum J, Nickoloff JA, Jasin M. 163.  1998. Gene conversion tracts from double-strand break repair in mammalian cells. Mol. Cell. Biol. 18:93–101 [Google Scholar]
  164. Beumer K, Bhattacharyya G, Bibikova M, Trautman JK, Carroll D. 164.  2006. Efficient gene targeting in Drosophila with zinc finger nucleases. Genetics 172:2391–403 [Google Scholar]
  165. Szczepek M, Brondani V, Büchel J, Serrano L, Segal DJ, Cathomen T. 165.  2007. Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases. Nat. Biotechnol. 25:786–93 [Google Scholar]
  166. Gupta A, Meng X, Zhu LJ, Lawson ND, Wolfe SA. 166.  2011. Zinc finger protein–dependent and –independent contributions to the in vivo off-target activity of zinc finger nucleases. Nucleic Acids Res. 39:381–92 [Google Scholar]
  167. Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA. 167.  et al. 2008. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat. Biotechnol. 26:808–16 [Google Scholar]
  168. Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD. 168.  2010. Genome editing with engineered zinc finger nucleases. Nat. Rev. Genet. 11:636–46 [Google Scholar]
  169. Pattanayak V, Ramirez CL, Joung JK, Liu DR. 169.  2011. Revealing off-target cleavage specificities of zinc-finger nucleases by in vitro selection. Nat. Methods 8:765–70 [Google Scholar]
  170. Doyon Y, Vo TD, Mendel MC, Greenberg SG, Wang J. 170.  et al. 2011. Enhancing zinc-finger-nuclease activity with improved obligate heterodimer architectures. Nat. Methods 8:74–79 [Google Scholar]
  171. Gabriel R, Lombardo A, Arens A, Miller JC, Genovese P. 171.  et al. 2011. An unbiased genome-wide analysis of zinc-finger nuclease specificity. Nat. Biotechnol. 29:816–23 [Google Scholar]
  172. Ding Q, Lee YK, Schaefer EA, Peters DT, Veres A. 172.  et al. 2013. A TALEN genome-editing system for generating human stem cell–based disease models. Cell Stem Cell 12:238–51 [Google Scholar]
  173. Hisano Y, Ota S, Arakawa K, Muraki M, Kono N. 173.  et al. 2013. Quantitative assay for TALEN activity at endogenous genomic loci. Biol. Open 2:363–67 [Google Scholar]
  174. Mussolino C, Morbitzer R, Lutge F, Dannemann N, Lahaye T, Cathomen T. 174.  2011. A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Res. 39:9283–93 [Google Scholar]
  175. Ousterout DG, Perez-Pinera P, Thakore PI, Kabadi AM, Brown MT. 175.  et al. 2013. Reading frame correction by targeted genome editing restores dystrophin expression in cells from Duchenne muscular dystrophy patients. Mol. Ther. 21:1718–26 [Google Scholar]
  176. Cradick TJ, Fine EJ, Antico CJ, Bao G. 176.  2013. CRISPR/Cas9 systems targeting β-globin and CCR5 genes have substantial off-target activity. Nucleic Acids Res. 41:9584–92 [Google Scholar]
  177. Fu Y, Foden JA, Khayter C, Maeder ML, Reyon D. 177.  et al. 2013. High-frequency off-target mutagenesis induced by CRISPR–Cas nucleases in human cells. Nat. Biotechnol. 31:822–26 [Google Scholar]
  178. Pattanayak V, Lin S, Guilinger JP, Ma E, Doudna JA, Liu DR. 178.  2013. High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity. Nat. Biotechnol. 31:839–43 [Google Scholar]
  179. Carroll D.178a.  2013. Staying on target with CRISPR-Cas. Nat. Biotechnol. 31:807–9 [Google Scholar]
  180. Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S. 179.  et al. 2013. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154:1380–89 [Google Scholar]
  181. Katsuyama T, Akmammedov A, Seimiya M, Hess SC, Sievers C, Paro R. 180.  2013. An efficient strategy for TALEN-mediated genome engineering in Drosophila. Nucleic Acids Res. 41:e163 [Google Scholar]
  182. Liu J, Li C, Yu Z, Huang P, Wu H. 181.  et al. 2012. Efficient and specific modifications of the Drosophila genome by means of an easy TALEN strategy. J. Genet. Genomics 39:209–15 [Google Scholar]
  183. Bassett AR, Tibbit C, Ponting CP, Liu J-L. 182.  2013. Highly efficient targeted mutagenesis of Drosophila with the CRISPR/Cas9 system. Cell Rep. 4:220–28 [Google Scholar]
  184. Gratz SJ, Cummings AM, Nguyen JN, Hamm DC, Donohue LK. 183.  et al. 2013. Genome engineering of Drosophila with the CRISPR RNA-guided Cas9 nuclease. Genetics 194:1029–35 [Google Scholar]
  185. Yu Z, Ren M, Wang Z, Zhang B, Rong YS. 184.  et al. 2013. Highly efficient genome modifications mediated by CRISPR/Cas9 in Drosophila. Genetics 195:289–91 [Google Scholar]
  186. Sander JD, Cade L, Khayter C, Reyon D, Peterson RT. 185.  et al. 2011. Targeted gene disruption in somatic zebrafish cells using engineered TALENs. Nat. Biotechnol. 29:697–98 [Google Scholar]
  187. Cade L, Reyon D, Hwang WY, Tsai SQ, Patel S. 186.  et al. 2012. Highly efficient generation of heritable zebrafish gene mutations using homo- and heterodimeric TALENs. Nucleic Acids Res. 40:8001–10 [Google Scholar]
  188. Chen S, Oikonomou G, Chiu CN, Niles BJ, Liu J. 187.  et al. 2013. A large-scale in vivo analysis reveals that TALENs are significantly more mutagenic than ZFNs generated using context-dependent assembly. Nucleic Acids Res. 41:2769–78 [Google Scholar]
  189. Moore FE, Reyon D, Sander JD, Martinez SA, Blackburn JS. 188.  et al. 2012. Improved somatic mutagenesis in zebrafish using transcription activator-like effector nucleases (TALENs). PLoS ONE 7:e37877 [Google Scholar]
  190. Chang N, Sun C, Gao L, Zhu D, Xu X. 189.  et al. 2013. Genome editing with RNA-guided Cas9 nuclease in zebrafish embryos. Cell Res. 23:465–72 [Google Scholar]
  191. Hwang WY, Fu Y, Reyon D, Maeder ML, Kaini P. 190.  et al. 2013. Heritable and precise zebrafish genome editing using a CRISPR–Cas system. PLoS ONE 8:e68708 [Google Scholar]
  192. Xiao A, Wu Y, Yang Z, Hu Y, Wang W. 191.  et al. 2013. EENdb: a database and knowledge base of ZFNs and TALENs for endonuclease engineering. Nucleic Acids Res. 41:D415–22 [Google Scholar]
  193. Jao LE, Wente SR, Chen W. 192.  2013. Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. Proc. Natl. Acad. Sci. USA 110:13904–9 [Google Scholar]
  194. Lloyd A, Plaisier CL, Carroll D, Drews GN. 193.  2005. Targeted mutagenesis using zinc-finger nucleases in Arabidopsis. Proc. Natl. Acad. Sci. USA 102:2232–37 [Google Scholar]
  195. Osakabe K, Osakabe Y, Toki S. 194.  2010. Site-directed mutagenesis in Arabidopsis using custom-designed zinc finger nucleases. Proc. Natl. Acad. Sci. USA 107:12034–39 [Google Scholar]
  196. Zhang F, Maeder ML, Unger-Wallace E, Hoshaw JP, Reyon D. 195.  et al. 2010. High frequency targeted mutagenesis in Arabidopsis thaliana using zinc finger nucleases. Proc. Natl. Acad. Sci. USA 107:12028–33 [Google Scholar]
  197. Jiang W, Zhou H, Bi H, Fromm M, Yang B, Weeks DP. 196.  2013. Demonstration of CRISPR/Cas9/sgRNA–mediated targeted gene modification in Arabidopsis, tobacco, sorghum and rice. Nucleic Acids Res. 41:e188 [Google Scholar]
  198. Capecchi MR.197.  2005. Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century. Nat. Rev. Genet. 6:507–12 [Google Scholar]
  199. Tesson L, Usal C, Menoret S, Leung E, Niles BJ. 198.  et al. 2011. Knockout rats generated by embryo microinjection of TALENs. Nat. Biotechnol. 29:695–96 [Google Scholar]
  200. Qiu Z, Liu M, Chen Z, Shao Y, Pan H. 199.  et al. 2013. High-efficiency and heritable gene targeting in mouse by transcription activator-like effector nucleases. Nucleic Acids Res. 41:e120 [Google Scholar]
  201. Shen B, Zhang J, Wu H, Wang J, Ma K. 200.  et al. 2013. Generation of gene-modified mice via Cas9/RNA-mediated gene targeting. Cell Res. 23:720–23 [Google Scholar]
  202. Wefers B, Meyer M, Ortiz O, Hrabé de Angelis M, Hansen J. 201.  et al. 2013. Direct production of mouse disease models by embryo microinjection of TALENs and oligodeoxynucleotides. Proc. Natl. Acad. Sci. USA 110:3782–87 [Google Scholar]
  203. Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW. 202.  et al. 2013. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell Rep. 153:910–18 [Google Scholar]
  204. Merlin C, Beaver LE, Taylor OR, Wolfe SA, Reppert SM. 203.  2013. Efficient targeted mutagenesis in the monarch butterfly using zinc-finger nucleases. Genome Res. 23:159–68 [Google Scholar]
  205. DiCarlo JE, Norville JE, Mali P, Rios X, Aach J, Church GM. 204.  2013. Genome engineering in Saccharomyces cerevisiae using CRISPR–Cas systems. Nucleic Acids Res. 41:4336–43 [Google Scholar]
  206. Townsend JA, Wright DA, Winfrey RJ, Fu F, Maeder ML. 205.  et al. 2009. High-frequency modification of plant genes using engineered zinc-finger nucleases. Nature 459:442–45 [Google Scholar]
  207. Zhang Y, Zhang F, Li X, Baller JA, Qi Y. 206.  et al. 2013. Transcription activator–like effector nucleases enable efficient plant genome engineering. Plant Physiol. 161:20–27 [Google Scholar]
  208. Shukla VK, Doyon Y, Miller JC, DeKelver RC, Moehle EA. 207.  et al. 2009. Precise genome modification in the crop species Zea mays using zinc-finger nucleases. Nature 459:437–41 [Google Scholar]
  209. Marton I, Zuker A, Shklarman E, Zeevi V, Tovkach A. 208.  et al. 2010. Nontransgenic genome modification in plant cells. Plant Physiol. 154:1079–87 [Google Scholar]
  210. Tan WS, Carlson DF, Walton MW, Fahrenkrug SC, Hackett PB. 209.  2012. Precision editing of large animal genomes. Adv. Genet. 80:37–97 [Google Scholar]
  211. Yu S, Luo J, Song Z, Ding F, Dai Y, Li N. 210.  2011. Highly efficient modification of beta-lactoglobulin (BLG) gene via zinc-finger nucleases in cattle. Cell Res. 21:1638–40 [Google Scholar]
  212. Ma S, Zhang S, Wang F, Liu Y, Liu Y. 211.  et al. 2012. Highly efficient and specific genome editing in silkworm using custom TALENs. PLoS ONE 7:e45035 [Google Scholar]
  213. Sajwan S, Takasu Y, Tamura T, Uchino K, Sezutsu H, Zurovec M. 212.  2013. Efficient disruption of endogenous Bombyx gene by TAL effector nucleases. Insect Biochem. Mol. Biol. 43:17–23 [Google Scholar]
  214. Takasu Y, Kobayashi I, Beumer K, Uchino K, Sezutsu H. 213.  et al. 2010. Targeted mutagenesis in the silkworm Bombyx mori using zinc-finger nuclease mRNA injections. Insect Biochem. Mol. Biol. 40:759–65 [Google Scholar]
  215. Wang Y, Li Z, Xu J, Zeng B, Ling L. 214.  et al. 2013. The CRISPR/Cas system mediates efficient genome engineering in Bombyx mori. Cell Res. 23:1414–16 [Google Scholar]
  216. Iizuka T, Sezutsu H, Tatematsu K, Kobayashi I, Yonemura N. 215.  et al. 2013. Colored fluorescent silk made by transgenic silkworms. Adv. Funct. Mater. 23:5232–39 [Google Scholar]
  217. DeGennaro M, McBride CS, Seeholzer L, Nakagawa T, Dennis EJ. 216.  et al. 2013. orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET. Nature 498:487–91 [Google Scholar]
  218. Aryan A, Anderson MA, Myles KM, Adelman ZN. 217.  2013. TALEN-based gene disruption in the dengue vector Aedes aegypti. PLoS ONE 8:e60082 [Google Scholar]
  219. Smidler AL, Terenzi O, Soichot J, Levashina EA, Marois E. 218.  2013. Targeted mutagenesis in the malaria mosquito using TALE nucleases. PLoS ONE 8:e74511 [Google Scholar]
  220. Liu PQ, Chan EM, Cost GJ, Zhang L, Wang J. 219.  et al. 2010. Generation of a triple-gene knockout mammalian cell line using engineered zinc-finger nucleases. Biotechnol. Bioeng. 106:97–105 [Google Scholar]
  221. Wang T, Wei JJ, Sabatini DM, Lander ES. 220.  2014. Genetic screens in human cells using the CRISPR/Cas9 system. Science 343:80–84 [Google Scholar]
  222. Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA. 221.  et al. 2014. Genome-scale CRISPR–Cas9 knockout screening in human cells. Science 343:84–87 [Google Scholar]
  223. Lombardo A, Cesana D, Genovese P, Di Stefano B, Provasi E. 222.  et al. 2011. Site-specific integration and tailoring of cassette design for sustainable gene transfer. Nat. Methods 8:861–69 [Google Scholar]
  224. Li H, Haurigot V, Doyon Y, Li T, Wong SY. 223.  et al. 2011. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature 475:217–21 [Google Scholar]
  225. Gutschner T, Baas M, Diederichs S. 224.  2011. Noncoding RNA gene silencing through genomic integration of RNA destabilizing elements using zinc finger nucleases. Genome Res. 21:1944–54 [Google Scholar]
  226. Hu R, Wallace J, Dahlem TJ, Grunwald DJ, O'Connell RM. 225.  2013. Targeting human microRNA genes using engineered Tal-effector nucleases (TALENs). PLoS ONE 8:e63074 [Google Scholar]
  227. Eyquem J, Poirot L, Galetto R, Scharenberg AM, Smith J. 226.  2013. Characterization of three loci for homologous gene targeting and transgene expression. Biotechnol. Bioeng. 110:2225–35 [Google Scholar]
  228. Hockemeyer D, Soldner F, Beard C, Gao Q, Mitalipova M. 227.  et al. 2009. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat. Biotechnol. 27:851–57 [Google Scholar]
  229. Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q. 228.  et al. 2011. Genetic engineering of human pluripotent cells using TALE nucleases. Nat. Biotechnol. 29:731–34 [Google Scholar]
  230. Lombardo A, Genovese P, Beausejour CM, Colleoni S, Lee YL. 229.  et al. 2007. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat. Biotechnol. 25:1298–306 [Google Scholar]
  231. Sebastiano V, Maeder ML, Angstman JF, Haddad B, Khayter C. 230.  et al. 2011. In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases. Stem Cells 29:1717–26 [Google Scholar]
  232. Yang L, Guell M, Byrne S, Yang JL, De Los Angeles A. 231.  et al. 2013. Optimization of scarless human stem cell genome editing. Nucleic Acids Res. 41:9049–61 [Google Scholar]
  233. Zou J, Maeder ML, Mali P, Pruett-Miller SM, Thibodeau-Beganny S. 232.  et al. 2009. Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell 5:97–110 [Google Scholar]
  234. Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu PQ. 233.  et al. 2011. Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478:391–94 [Google Scholar]
  235. Maier DA, Brennan AL, Jiang S, Binder-Scholl GK, Lee G. 234.  et al. 2013. Efficient clinical scale gene modification via zinc finger nuclease–targeted disruption of the HIV co-receptor CCR5. Hum. Gene Ther. 24:245–58 [Google Scholar]
  236. Li L, Krymskaya L, Wang J, Henley J, Rao A. 235.  et al. 2013. Genomic editing of the HIV-1 coreceptor CCR5 in adult hematopoietic stem and progenitor cells using zinc finger nucleases. Mol. Ther. 21:1259–69 [Google Scholar]
  237. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N. 236.  et al. 2003. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–19 [Google Scholar]
  238. DeKelver RC, Choi VM, Moehle EA, Paschon DE, Hockemeyer D. 237.  et al. 2010. Functional genomics, proteomics, and regulatory DNA analysis in isogenic settings using zinc finger nuclease–driven transgenesis into a safe harbor locus in the human genome. Genome Res. 20:1133–42 [Google Scholar]
  239. Yuan J, Wang J, Crain K, Fearns C, Kim KA. 238.  et al. 2012. Zinc-finger nuclease editing of human cxcr4 promotes HIV-1 CD4+ T cell resistance and enrichment. Mol. Ther. 20:849–59 [Google Scholar]
  240. Torikai H, Reik A, Soldner F, Warren EH, Yuen C. 239.  et al. 2013. Towards eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122:1341–49 [Google Scholar]
  241. Hou Z, Zhang Y, Propson NE, Howden SE, Chu LF. 240.  et al. 2013. Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis. Proc. Natl. Acad. Sci. USA 110:15644–49 [Google Scholar]
  242. de Lange O, Schreiber T, Schandry N, Radeck J, Braun KH. 241.  et al. 2013. Breaking the DNA-binding code of Ralstonia solanacearum TAL effectors provides new possibilities to generate plant resistance genes against bacterial wilt disease. New Phytol. 199:773–86 [Google Scholar]
  243. Watanabe T, Ochiai H, Sakuma T, Horch HW, Hamaguchi N. 242.  et al. 2012. Non-transgenic genome modifications in a hemimetabolous insect using zinc-finger and TAL effector nucleases. Nat. Commun. 3:1017 [Google Scholar]
  244. Ochiai H, Fujita K, Suzuki K, Nishikawa M, Shibata T. 243.  et al. 2010. Targeted mutagenesis in the sea urchin embryo using zinc-finger nucleases. Genes Cells 15:875–85 [Google Scholar]
  245. Hosoi S, Sakuma T, Sakamoto N, Yamamoto T. 244.  2014. Targeted mutagenesis in sea urchin embryos using TALENs. Dev. Growth Differ. 56:92–97 [Google Scholar]
  246. Kawai N, Ochiai H, Sakuma T, Yamada L, Sawada H. 245.  et al. 2012. Efficient targeted mutagenesis of the chordate Ciona intestinalis genome with zinc-finger nucleases. Dev. Growth Differ. 54:535–45 [Google Scholar]
  247. Treen N, Yoshida K, Sakuma T, Sasaki H, Kawai N. 246.  et al. 2014. Tissue-specific and ubiquitous gene knockouts by TALEN electroporation provide new approaches to investigating gene function in Ciona. Development 141:481–87 [Google Scholar]
  248. Straimer J, Lee MC, Lee AH, Zeitler B, Williams AE. 247.  et al. 2012. Site-specific genome editing in Plasmodium falciparum using engineered zinc-finger nucleases. Nat. Methods 9:993–98 [Google Scholar]
  249. Ansai S, Ochiai H, Kanie Y, Kamei Y, Gou Y. 248.  et al. 2012. Targeted disruption of exogenous EGFP gene in medaka using zinc-finger nucleases. Dev. Growth Differ. 54:546–56 [Google Scholar]
  250. Ansai S, Sakuma T, Yamamoto T, Ariga H, Uemura N. 249.  et al. 2013. Efficient targeted mutagenesis in medaka using custom-designed transcription activator–like effector nucleases. Genetics 193:739–49 [Google Scholar]
  251. Dong Z, Ge J, Li K, Xu Z, Liang D. 250.  et al. 2011. Heritable targeted inactivation of myostatin gene in yellow catfish (Pelteobagrus fulvidraco) using engineered zinc finger nucleases. PLoS ONE 6:e28897 [Google Scholar]
  252. Yano A, Guyomard R, Nicol B, Jouanno E, Quillet E. 251.  et al. 2012. An immune-related gene evolved into the master sex-determining gene in rainbow trout, Oncorhynchus mykiss. Curr. Biol. 22:1423–28 [Google Scholar]
  253. Young JJ, Cherone JM, Doyon Y, Ankoudinova I, Faraji FM. 252.  et al. 2011. Efficient targeted gene disruption in the soma and germ line of the frog Xenopus tropicalis using engineered zinc-finger nucleases. Proc. Natl. Acad. Sci. USA 108:7052–57 [Google Scholar]
  254. Lei Y, Guo X, Liu Y, Cao Y, Deng Y. 253.  et al. 2012. Efficient targeted gene disruption in Xenopus embryos using engineered transcription activator–like effector nucleases (TALENs). Proc. Natl. Acad. Sci. USA 109:17484–89 [Google Scholar]
  255. Ishibashi S, Cliffe R, Amaya E. 254.  2012. Highly efficient bi-allelic mutation rates using TALENs in Xenopus tropicalis. Biol. Open 1:1273–76 [Google Scholar]
  256. Blitz IL, Biesinger J, Xie X, Cho KW. 255.  2013. Biallelic genome modification in F0 Xenopus tropicalis embryos using the CRISPR/Cas system. Genesis 51:827–34 [Google Scholar]
  257. Guo X, Zhang T, Hu Z, Zhang Y, Shi Z. 256.  et al. 2014. Efficient RNA/Cas9-mediated genome editing in Xenopus tropicalis. Development 141:707–14 [Google Scholar]
  258. Nakayama T, Fish MB, Fisher M, Oomen-Hajagos J, Thomsen GH, Grainger RM. 257.  2013. Simple and efficient CRISPR/Cas9-mediated targeted mutagenesis in Xenopus tropicalis. Genesis 51:835–43 [Google Scholar]
  259. Li W, Teng F, Li T, Zhou Q. 258.  2013. Simultaneous generation and germline transmission of multiple gene mutations in rat using CRISPR–Cas systems. Nat. Biotechnol. 31:684–86 [Google Scholar]
  260. Tong C, Huang G, Ashton C, Wu H, Yan H, Ying QL. 259.  2012. Rapid and cost-effective gene targeting in rat embryonic stem cells by TALENs. J. Genet. Genomics 39:275–80 [Google Scholar]
  261. Li D, Qiu Z, Shao Y, Chen Y, Guan Y. 260.  et al. 2013. Heritable gene targeting in the mouse and rat using a CRISPR–Cas system. Nat. Biotechnol. 31:681–83 [Google Scholar]
  262. Goldberg AD, Banaszynski LA, Noh K-M, Lewis PW, Elsässer SJ. 261.  et al. 2010. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell Stem Cell 140:678–91 [Google Scholar]
  263. Connelly JP, Barker JC, Pruett-Miller S, Porteus MH. 262.  2010. Gene correction by homologous recombination with zinc finger nucleases in primary cells from a mouse model of a generic recessive genetic disease. Mol. Ther. 18:1103–10 [Google Scholar]
  264. Flisikowska T, Thorey IS, Offner S, Ros F, Lifke V. 263.  et al. 2011. Efficient immunoglobulin gene disruption and targeted replacement in rabbit using zinc finger nucleases. PLoS ONE 6:e21045 [Google Scholar]
  265. Song J, Zhong J, Guo X, Chen Y, Zou Q. 264.  et al. 2013. Generation of RAG 1- and 2-deficient rabbits by embryo microinjection of TALENs. Cell Res. 23:1059–62 [Google Scholar]
  266. Xiong K, Li S, Zhang H, Cui Y, Yu D. 265.  et al. 2013. Targeted editing of goat genome with modular-assembly zinc finger nucleases based on activity prediction by computational molecular modeling. Mol. Biol. Rep. 40:4251–56 [Google Scholar]
  267. Tan W, Carlson DF, Lancto CA, Garbe JR, Webster DA. 266.  et al. 2013. Efficient nonmeiotic allele introgression in livestock using custom endonucleases. Proc. Natl. Acad. Sci. USA 110:16526–31 [Google Scholar]
  268. Song X, Sato Y, Felemban A, Ito A, Hossain M. 267.  et al. 2012. Equarin is involved as an FGF signaling modulator in chick lens differentiation. Dev. Biol. 368:109–17 [Google Scholar]
  269. Doyon JB, Zeitler B, Cheng J, Cheng AT, Cherone JM. 268.  et al. 2011. Rapid and efficient clathrin-mediated endocytosis revealed in genome-edited mammalian cells. Nat. Cell Biol. 13:331–37 [Google Scholar]
  270. Ding Q, Regan SN, Xia Y, Oostrom LA, Cowan CA, Musunuru K. 269.  2013. Enhanced efficiency of human pluripotent stem cell genome editing through replacing TALENs with CRISPRs. Cell Stem Cell 12:393–94 [Google Scholar]
  271. Curtin SJ, Zhang F, Sander JD, Haun WJ, Starker C. 270.  et al. 2011. Targeted mutagenesis of duplicated genes in soybean with zinc-finger nucleases. Plant Physiol. 156:466–73 [Google Scholar]
  272. Li T, Liu B, Spalding MH, Weeks DP, Yang B. 271.  2012. High-efficiency TALEN-based gene editing produces disease-resistant rice. Nat. Biotechnol. 30:390–92 [Google Scholar]
  273. Shan Q, Wang Y, Chen K, Liang Z, Li J. 272.  et al. 2013. Rapid and efficient gene modification in rice and Brachypodium using TALENs. Mol. Plant 6:1365–68 [Google Scholar]
  274. Shan Q, Wang Y, Li J, Zhang Y, Chen K. 273.  et al. 2013. Targeted genome modification of crop plants using a CRISPR–Cas system. Nat. Biotechnol. 31:686–88 [Google Scholar]
  275. Sun Z, Li N, Huang G, Xu J, Pan Y. 274.  et al. 2013. Site-specific gene targeting using transcription activator–like effector (TALE)-based nuclease in Brassica oleracea. J. Integr. Plant Biol. 55:1092–103 [Google Scholar]
  276. Wendt T, Holm PB, Starker CG, Christian M, Voytas DF. 275.  et al. 2013. TAL effector nucleases induce mutations at a pre-selected location in the genome of primary barley transformants. Plant Mol. Biol. 83:279–85 [Google Scholar]
  277. Upadhyay SK, Kumar J, Alok A, Tuli R. 276.  2013. RNA-guided genome editing for target gene mutations in wheat. G3 3:2233–38 [Google Scholar]
  278. Nekrasov V, Staskawicz B, Weigel D, Jones JD, Kamoun S. 277.  2013. Targeted mutagenesis in the model plant Nicotiana benthamiana using Cas9 RNA-guided endonuclease. Nat. Biotechnol. 31:691–93 [Google Scholar]
  279. Li JF, Norville JE, Aach J, McCormack M, Zhang D. 278.  et al. 2013. Multiplex and homologous recombination–mediated genome editing in Arabidopsis and Nicotiana benthamiana using guide RNA and Cas9. Nat. Biotechnol. 31:688–91 [Google Scholar]
  280. Sizova I, Greiner A, Awasthi M, Kateriya S, Hegemann P. 279.  2013. Nuclear gene targeting in Chlamydomonas using engineered zinc-finger nucleases. Plant J. 73:873–82 [Google Scholar]
  281. Santiago Y, Chan E, Liu P-Q, Orlando S, Zhang L. 280.  et al. 2008. Targeted gene knockout in mammalian cells by using engineered zinc-finger nucleases. Proc. Natl. Acad. Sci. USA 105:5809–14 [Google Scholar]
  282. Jiang W, Bikard D, Cox D, Zhang F, Marraffini LA. 281.  2013. RNA-guided editing of bacterial genomes using CRISPR–Cas systems. Nat. Biotechnol. 31:233–39 [Google Scholar]
  283. Cradick TJ, Keck K, Bradshaw S, Jamieson AC, McCaffrey AP. 282.  2010. Zinc-finger nucleases as a novel therapeutic strategy for targeting hepatitis B virus DNAs. Mol. Ther. 18:947–54 [Google Scholar]
  284. Bloom K, Ely A, Mussolino C, Cathomen T, Arbuthnot P. 283.  2013. Inactivation of hepatitis B virus replication in cultured cells and in vivo with engineered transcription activator–like effector nucleases. Mol. Ther. 21:1889–97 [Google Scholar]
  285. Qu X, Wang P, Ding D, Li L, Wang H. 284.  et al. 2013. Zinc-finger-nucleases mediate specific and efficient excision of HIV-1 proviral DNA from infected and latently infected human T cells. Nucleic Acids Res. 41:7771–82 [Google Scholar]
  286. Ebina H, Misawa N, Kanemura Y, Koyanagi Y. 285.  2013. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. Sci. Rep. 3:2510 [Google Scholar]
  287. Segal DJ, Meckler JF. 286.  2013. Genome engineering at the dawn of the golden age. Annu. Rev. Genomics Hum. Genet. 14:135–58 [Google Scholar]
/content/journals/10.1146/annurev-biochem-060713-035418
Loading
/content/journals/10.1146/annurev-biochem-060713-035418
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error