Project description
Understanding how conflict resolution in the genome fails in some diseases
Transcription (creating RNA from the DNA code) and replication (creating a DNA copy from the existing DNA) occur frequently in cells. They use the same DNA 'template', but the processes can move along it in different directions and at different rates. Encounters or collisions can cause transcription–replication conflicts (TRCs), DNA damage and genomic instability. One reason for these TRCs is the existence of G-quadruplexes (G4, secondary DNA structures) and RNA–DNA hybrids (R-loops), which can pose a barrier to replication fork progression. Cells have developed strategies to address these TRCs, yet the mechanisms by which cells respond to G4/R-loop-induced TRCs are largely unknown. The EU-funded GLoopID project is using novel techniques to answer open questions with potential application in targeted therapies for diseases such as cancer and some genetic disorders.
Objective
Maintenance of genome stability is challenged by obstacles that interfere with normal progression of essential DNA-associated transactions, such as DNA replication and transcription. One such obstacle is the G-quadruplex (G4) DNA secondary structure, which can form in G-rich repetitive DNA sequences. Transcribed G4-DNA loci often co-exist with stable RNA-DNA hybrids (R-loops), potentially causing deleterious transcription-replication conflicts (TRCs). Therefore, the ability of cells to mitigate TRCs formation is critical for cell and organismal fitness. While the pathways involved in repairing other DNA lesions are relatively well understood, the mechanisms by which cells respond to G4/R-loop-induced TRCs remain uncharted, largely due to a lack of efficient approaches for inducing site-specific G4s/R-loops into the genome. Several studies reported dedicated helicases capable of unwinding G4s/R-loops, yet whether additional factors exist and how different types of TRCs are resolved remains unknown. In this project, I aim to dissect the fundamental mechanisms that protect cells from TRCs at DNA loci harbouring G4s/R-loops. To do so, I will establish a novel system with site-specific G4/R-loop substrates in living cells and I will systematically investigate their protein composition to identify novel factors in G4/R-loop metabolism. I will further examine the genetic vulnerabilities of candidate G4/R-loop helicase-deficient cells and the regulatory mechanisms underlying G4/R-loop unwinding by these helicases. As mutations in several G4/R-loop helicases predispose to various cancers and genetic disorders, a detailed understanding of the basic mechanisms controlling G4/R-loop removal is of utmost importance, and will shed light on disease aetiology and the rational development of more targeted therapeutic strategies.
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
You need to log in or register to use this function
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.
-
H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
See all projects funded under this programme -
H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
See all projects funded under this programme
Topic(s)
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.
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.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
See all projects funded under this funding scheme
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2019
See all projects funded under this callCoordinator
Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
NW1 1AT London
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.