Project description
Mechanisms of homologous recombination in mitosis and meiosis
Homologous recombination, in which nucleotide sequences are exchanged between two similar or identical DNA molecules, is widely used to repair harmful double-strand breaks, or DSBs, in DNA. To enable this, cells must search for and identify an intact homologous template DNA molecule in the genome. Despite the critical importance of this homology search for genome maintenance (mitosis) and sexual reproduction (meiosis), the mechanisms are poorly understood. The ERC-funded Homologic project aims to investigate the hypothesis that chromatin composition and mechanical motion provide cues for search simplification and regulation during both processes. Genetic engineering, large synthetic chromosomal regions and novel genomic and molecular approaches should shed light on homologous recombination in mitosis and meiosis.
Objective
DNA double-strand breaks (DSB) repair by homologous recombination (HR) entails identification of an intact homologous template DNA molecule in the genome. Homology search is guided by the DSB-flanking ssDNA sequence assembled into a RecA-family nucleoprotein filament (NPF). A biased version of this process, regulated in an ill-defined manner by chromosomes’ structure and meiosis-specific HR proteins, also underlies homolog recognition and recombination during meiosis I in most examined eukaryotes. Despite its centrality for genome maintenance and sexual reproduction, how homology search operates in cells and the nature of its meiotic regulations are largely unknown. Our goal is to solve these two major biological conundrums with a simple idea: that substrate properties (chromatin composition and motion) provide cues for search simplification and regulation.
First, we will address the existence of a homology search facilitation mechanism based on combined (i) DNA occlusion by nucleosome and (ii) seeding of homology search by pioneer transcription factors (WP1). These insights will be applied to accelerate yeast evolution and improve gene-editing. Second, we will address how uncoordinated movements of semi-rigid meiotic chromosomes can generate mechanical cues underlying HR regulations that result in patterned recombination between homologs (WP2). The experimental strategy will involve extensive genetic engineering and large synthetic chromosomal regions for targeted alteration of chromatin composition, chromosome physical properties and chromosome motion in cis. Novel genomic and molecular approaches we developed to directly detect transient HR intermediates in yeast make this project uniquely feasible. This work should elucidate enigmatic interplays between chromosome biology and conserved DNA metabolic processes in mitosis and meiosis, broadens the current paradigm of facilitated target search by proteins in DNA, and yield tools of broad biotechnological interest.
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 heredity
- natural sciences biological sciences genetics chromosomes
- 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.
-
HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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.
HORIZON-ERC - HORIZON ERC Grants
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) ERC-2024-COG
See all projects funded under this callHost institution
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.
75794 PARIS
France
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.