Basic structure and design of a zinc finger nuclease (ZFN). ZFNs are created by joining a DNA-binding region to the catalytic domain of the nonspecific Fok1 endonuclease. Zinc fingers are a protein motif capable of DNA binding, whose sequence specificity can be predetermined. Each zinc finger, illustrated by an individual circle, recognizes 3-4 nucleotides, and, by assembling three or four suitable zinc finger motifs, a sequence-specific DNA-binding domain can be created. Fok1 nuclease activity requires dimerization, and so the customized ZFNs function in pairs. As shown, the zinc finger-binding domain brings two Fok1 units together in the right orientation over the target sequence; this induces Fok1 dimerization and target sequence cleavage.