Genome maintenance and evolution

Description du projet

L’évolution à la rescousse: le paradigme de la maintenance du génome

Une réplication fidèle de l’ADN est vitale pour le maintien de l’intégrité du génome et des cellules. Divers facteurs exogènes et endogènes peuvent toutefois provoquer un stress réplicatif et entraîner des cancers et des défauts de développement. L’hypothèse de travail du projet GENMAINEVO, financé par l’UE, est que les cellules répondent au stress de réplication par l’acquisition de mutations qui les aident à adapter leur aptitude. Les chercheurs utiliseront la levure bourgeonnante Saccharomyces cerevisiae comme organisme modèle pour étudier, par le biais de l’évolution dirigée, la manière dont les cellules répondent aux perturbations de la maintenance du génome aux niveaux du génome et de la biologie. Les résultats apporteront des connaissances importantes sur les mécanismes évolutifs et la manière dont ils peuvent sauver des processus cellulaires clés tels que la maintenance du génome.

Objectif

Genome maintenance describes a subset of conserved cellular processes responsible for the faithful propagation of genomes across cell divisions. Defects in genome maintenance have been associated with several medical disorders such as cancer, aging and developmental defects. Recently we showed how perturbations in DNA replication, one of the most conserved processes in genome maintenance, induce an evolutionary process that leads to the sequential and concerted accumulation of adaptive mutations that increase the cellular fitness in response to replication stress. To what extent this fast-evolutionary rescue applies to other defects in genome maintenance, and what evolutionary trajectories are responsible for adaptation under different cellular stresses remain unexplored questions. Furthermore, while adaptive mutations rewire genetic networks to achieve increased fitness, their pleiotropic effect on cell biology is unknown. Here I propose a plan to comprehensively investigate these questions by taking advantage of a multi-disciplinary methodology using the budding yeast S. cerevisiae as a eukaryotic model organism. Experimental evolution of cells perturbed in several aspects of genome maintenance will be combined with computational and quantitative approaches to study their evolutionary adaptation in response to the different initial perturbations. Molecular genetics and cell biology techniques will be then used to investigate the consequence of these adaptations to cell’s sensitivity to genotoxic agents, a phenotype directly relevant for the treatment of medical-relevant diseases including cancer and infection diseases. The knowledge generated by the proposed research project will reveal important aspects of how cells adapt to genetic perturbations, with implications for both medical therapies and evolutionary cell biology at large.