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Understanding DNA interstrand crosslink repair – the Fanconi anemia pathway and beyond

Project description

A novel DNA repair pathway

Interstrand crosslinks (ICLs) are a form of DNA damage in which the strands are chemically linked, preventing normal DNA replication and transcription. ICLs are conventionally recognised and repaired through a biochemical pathway known as the Fanconi anaemia DNA repair pathway. Scientists of the EU-funded XlinkRepair project have identified a novel pathway that repairs endogenous ICLs. For the duration of the project, they will investigate the molecular mechanism of this pathway and unveil key factors, mutagenic consequences and chromatin dynamics. Results will provide important insight into the maintenance of genome integrity and increase our understanding of the rare inherited condition Fanconi anaemia.

Objective

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.

Keywords

Host institution

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Net EU contribution
€ 2 000 000,00
Address
KLOVENIERSBURGWAL 29 HET TRIPPENHUIS
1011 JV AMSTERDAM
Netherlands

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Region
West-Nederland Noord-Holland Groot-Amsterdam
Activity type
Research Organisations
Links
Total cost
€ 2 000 000,00

Beneficiaries (1)