retrovolution hiv–driven evolution of cellular genes and improvement of anticancer drug activationretrovolution hiv-driven细胞基因的进化和改善抗癌药物激活.pdfVIP

Retrovolution: HIV–Driven Evolution of Cellular Genes and Improvement of Anticancer Drug Activation 1 1 1,2 3,4,5 1 Paola Rossolillo , Flore Winter , Etienne Simon-Loriere , Sarah Gallois-Montbrun , Matteo Negroni * ´ ´ ´ ´ ´ 1 Architecture et Reactivite de l’ARN, Universite de Strasbourg, CNRS, IBMC, Strasbourg, France, 2 Institut Pasteur, Unite de Genetique Fonctionnelle de Maladies ´ ´ Infectieuses, Paris, France, 3 Inserm, U1016, Institut Cochin, Paris, France, 4 CNRS, UMR8104, Paris, France, 5 Universite Paris Descartes, Sorbonne Paris Cite, Paris, France Abstract In evolution strategies aimed at isolating molecules with new functions, screening for the desired phenotype is generally performed in vitro or in bacteria. When the final goal of the strategy is the modification of the human cell, the mutants selected with these preliminary screenings may fail to confer the desired phenotype, due to the complex networks that regulate gene expression in higher eukaryotes. We developed a system where, by mimicking successive infection cycles with HIV-1 derived vectors containing the gene target of the evolution in their genome, libraries of gene mutants are generated in the human cell, where they can be directly screened. As a proof of concept we created a library of mutants of the human deoxycytidine kinase (dCK) gene, involved in the activation of nucleoside analogues used in cancer treatment,