2008/12/05

Custom meganucleases induce chromosomal gene repair without detectable genotoxicity.

Custom meganucleases that recognize and cleave a specific sequence of the human xeroderma pigmentosum gene induce chromosomal gene repair without detectable genotoxicity; the paper on the subject has been published recently in Nature. The structure of the nuclease/DNA complexes shows how the specific recognition of the DNA by the heterodimeric nucleases is achieved at the molecular level. This work raises new possibilities for gene therapy in patients with xeroderma pigmentosum and other monogenic diseases that could be treated ex vivo. Meganucleases recognize long DNA sequences (between 14 and 40 bp, hence their name) and thus can cleave single sites in whole genomes. This unique property allow to develop them into potent tools for gene targeting by tailoring their specificity, which can be accomplished by protein engineering and high throughput screening methods. When the target is a defective gene, and a DNA matrix with the correct gene sequence is also introduced in the cells, the double strand break induces a homologous recombination event that repairs the gene and restores its functionality. The work was done by the Macromolecular Crystallography and the NMR groups of the Centro Nacional de Investigaciones Oncológicas, in collaboration with researchers from the company Cellectis and the Centre de Regulació Genómica. Novel meganucleases of biomedical interest are currently being studied at the Structural Biology Unit of CICbioGUNE in collaboration with these institutions.