Molecular basis of xeroderma pigmentosum group C DNA recognition by engineered meganucleases

Pilar Redondo, Jesús Prieto, Inés G. Muñoz, Andreu Alibés, Francois Stricher, Luis Serrano, Jean-Pierre Cabaniols, Fayza Daboussi, Sylvain Arnould, Christophe Perez, Philippe Duchateau, Frédéric Pâques, Francisco J. Blanco () and Guillermo Montoya ()
Additional contact information
Pilar Redondo: Macromolecular Crystallography Group,
Jesús Prieto: NMR group, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), c/Melchor Fdez. Almagro 3, 28029 Madrid, Spain
Inés G. Muñoz: Macromolecular Crystallography Group,
Andreu Alibés: European Molecular Biology Laboratory (EMBL)-CRG Systems Biology Unit, Centre de Regulació Genòmica (CRG), Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
Francois Stricher: European Molecular Biology Laboratory (EMBL)-CRG Systems Biology Unit, Centre de Regulació Genòmica (CRG), Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
Luis Serrano: European Molecular Biology Laboratory (EMBL)-CRG Systems Biology Unit, Centre de Regulació Genòmica (CRG), Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
Jean-Pierre Cabaniols: CELLECTIS S.A., 102 Avenue Gaston Roussel, 93235 Romainville, France
Fayza Daboussi: CELLECTIS S.A., 102 Avenue Gaston Roussel, 93235 Romainville, France
Sylvain Arnould: CELLECTIS S.A., 102 Avenue Gaston Roussel, 93235 Romainville, France
Christophe Perez: CELLECTIS S.A., 102 Avenue Gaston Roussel, 93235 Romainville, France
Philippe Duchateau: CELLECTIS S.A., 102 Avenue Gaston Roussel, 93235 Romainville, France
Frédéric Pâques: CELLECTIS S.A., 102 Avenue Gaston Roussel, 93235 Romainville, France
Francisco J. Blanco: NMR group, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), c/Melchor Fdez. Almagro 3, 28029 Madrid, Spain
Guillermo Montoya: Macromolecular Crystallography Group,

Nature, 2008, vol. 456, issue 7218, 107-111

Abstract: For the gene therapy toolkit Homing endonucleases or 'meganucleases' are a type of very rare-cutting endonuclease. They recognize much larger DNA sequences than do 'classical' restriction enzymes, so they produce a low frequency of cleavage in the human genome. This makes them of interest for gene therapy, as highly specific molecular scalpels to target specific genes. In a proof-of-principle experiment, Redondo et al. have engineered homing endonucleases with the potential to aid the repair of the gene mutated in xeroderma pigmentosum, a disorder that affects the nucleotide excision repair machinery, compromising the body's ability to remove damage caused by ultraviolet light. Xeroderma pigmentosum patients have high frequencies of mutations and hence a high predisposition to develop skin cancer. The newly designed enzymes, called Amel3–4 and Ini3–4, are derivatives of the homing endonuclease I-CreI that cleave the human XPC gene both in vitro and in vivo. Structural analysis suggests that their catalytic mechanism of cleavage is similar to that of the wild type homodimeric I-CreI, and both Amel3–4 and Ini3–4 induce high levels of gene targeting in mammalian cells. This work demonstrates a gene repair technology with the potential to repair genes in xeroderma pigmentosum that produce other monogenetic diseases.

Date: 2008
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DOI: 10.1038/nature07343

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