Description du projet
Une nouvelle voie de réparation de l’ADN
Les ponts intercaténaires sont une forme de lésion de l’ADN dans laquelle les brins forment entre eux des liaisons chimiques, ce qui empêche la réplication et la transcription normales de l’ADN. Les ponts intercaténaires sont habituellement reconnus et réparés par le biais d’une voie biochimique appelée voie de réparation de l’ADN dans le cadre de l’anémie de Fanconi. Les scientifiques du projet XlinkRepair, financé par l’UE, ont identifié une nouvelle voie qui répare les ponts intercaténaires endogènes. Pendant toute la durée du projet, ils étudieront le mécanisme moléculaire de cette voie et en dévoileront les facteurs clés, les conséquences mutagènes et la dynamique de la chromatine. Les résultats fourniront des connaissances précieuses sur l’entretien de l’intégrité du génome et renforceront notre compréhension de l’anémie de Fanconi, une maladie héréditaire rare.
Objectif
DNA interstrand crosslinks (ICLs) are toxic DNA lesions that are induced by cancer chemotherapeutics but are also formed endogenously. ICL repair is mostly linked to DNA replication, which complicated the biochemical dissection of this process. The classical ICL repair pathway is the Fanconi anemia pathway, affected in the cancer predisposition syndrome Fanconi anemia (FA). Although the repair mechanism is poorly understood, recent studies have revealed unanticipated insights that now allow us to address key questions. While the FA pathway was long thought to be the only replication-coupled ICL repair pathway, two novel pathways were recently discovered. We described one novel pathway that repairs endogenous ICLs induced by acetaldehyde, a product of alcohol metabolism. However, mechanistic details of this novel pathway are lacking. Other unexplored aspects are the role of the chromatin context and the mutagenic consequences of repair. Here, I will capitalize on my group’s expertise applying a unique biochemical system that recapitulates ICL repair, and combine this with newly developed tools to address these objectives: 1) We will decipher key steps in the FA pathway of ICL repair. We will resolve the roles(s) of the FA core complex and the direct function of FANCI-FANCD2 ubiquitination, a key activating step. 2) We will move into new directions and investigate FA-independent ICL repair pathways. We will determine the molecular mechanism of acetaldehyde ICL repair and investigate the repair mechanisms of other aldehyde-induced ICLs. 3) We will extend our knowledge beyond the direct repair factors by defining chromatin dynamics during ICL repair and determining its role. In addition, we will delineate the mutagenicity of ICL repair to evaluate its consequences. These studies will provide important novel insights into how cells maintain genome integrity, increase our understanding of Fanconi anemia, and may improve strategies in chemotherapeutic treatment.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
1011 JV AMSTERDAM
Pays-Bas