Project description
DNA repair decisions
To maintain genomic integrity, cells have evolved mechanisms that repair DNA damage, especially double strand breaks (DSBs) which are the most dangerous. There are two pathways implicated in DNA repair: non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ directly ligates broken DNA ends, while HR uses a homologous DNA sequence as a template to repair the DSBs. With the support of the Marie Skłodowska-Curie Actions programme, the CC-DNArep project aims to understand how cells decide on which pathway to use. The work will explore the role of the CCAR2 protein in DNA repair decisions and study its interaction with other molecules. Project results will provide important insight into the DNA repair pathway with potential implications for cancer therapy.
Objective
Ensuring cellular integrity and genome stability requires tight control of DNA damage repair. Defects in the processes involved lead to the accumulation of mutations that might cause various diseases, including cancer. DNA double-strand break (DSB) is the most severe type of DNA damage, and two main pathways exist to repair it. The non-homologous end joining (NHEJ) is an error-prone repair pathway with little or no DNA processing, which results in mutations of DNA sequences at the repair site. Alternatively, Homologous Recombination (HR) ensures an error-free repair by using the information present in homolog sequences. Thus, maintaining the HR:NHEJ balance and precise regulation of these pathways is essential for cell fitness. Upon DSB, CtIP is recruited to the damaged site and promotes DNA end resection, required to initiate HR. Recently, CCAR2 was identified as an antagonist interactor of CtIP, therefore promoting NHEJ. CCAR2 is a protein without defined catalytic activity but with several functional domains known to interact with other protein partners. However, how CCAR2 binding regulates CtIP activity on DNA damage repair remains elusive. In this project, I propose to study this interaction by a multidisciplinary approach. Biochemical and biophysical single-molecule fluorescent studies will be applied to understand the regulatory function of CCAR2 upon interaction with CtIP. These will be combined with molecular dynamics simulations to obtain further insights into their direct interaction and how different ligands affect the stability of the CCAR2-CtIP complex. Moreover, in vitro findings will be complemented with experiments in human cell lines upon induced DNA damage. Altogether, this project will provide a full mechanistic understanding of CCAR2-mediated regulation of CtIP activity in the cell. This will shed light on essential information regarding how the HR:NHEJ balance can be modulated, which could have an impact on the treatment of several diseases.
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
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences genetics genomes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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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.
Funding Scheme
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.
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.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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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) HORIZON-MSCA-2024-PF-01
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41004 Sevilla
Spain
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