Cover: Meganucleases are sequence-speci.c endonucleases with large cleavage sites that can be used to induce e.cient homologous gene targeting in cultured cells and plants. These enzymes open novel perspectives for genome engineering in a wide range of .elds, including gene therapy. A new crystal structure of the I-CreI dimer without DNA has allowed the comparison with the DNA bound protein. This comparison reveals the important role of the C-terminal loop in DNA binding and cleavage. Two regions in that loop (Ser138-Lys139 and Lys142-Thr143) are essential for DNA binding in vitro and abolish cleavage in vivo; demonstrating that the C-terminal loop of I-CreI endonuclease plays a fundamental role in its catalytic mechanism and suggest this novel site as a region to take into account for engineering new endonucleases with tailored speci.city (for details, see Prieto et al. (2007) Nucleic Acids Res.,
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