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(57) Abstract : The present invention concerns novel methods for improving cleavage of DNA by rare-cutting endonucleases, overcoming DNA modification constraints, particularly DNA methylation, thereby giving new tools for genome engineering, par- ticularly to increase the integration efficiency of a transgene into a genome at a predetermined location, including therapeutic ap- plications and cell line engineering. II Ill (88) Date of publication of the international search report : May 2012