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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- medical and health sciences clinical medicine oncology
- natural sciences chemical sciences organic chemistry alcohols
- medical and health sciences clinical medicine hematology
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2020-COG
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1011 JV AMSTERDAM
Netherlands
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