Summary
Homology-directed repair is an essential, evolutionary conserved DNA repair pathway that accurately restores genetic information lost due to double-stranded breaks. Its key step is the ‘homology search’, where the broken DNA end locates its matching sequence, typically located on a sister chromatid, to use as a repair template. Despite its significance, the biophysical mechanism of this search within the complex environment of vertebrate genomes remains debated. Emerging hypotheses propose that this search is driven by ‘nucleoprotein’ filaments comprised of repair proteins bound to the broken DNA ends, that actively traverse the nuclear space to find and recognize homologous sequences. We will explore this mechanism by developing quantitative biophysical models that integrate the latest experimental insights on the 3D architecture of sister chromatids and dynamics of nucleoprotein filaments. Our specific aims are: (1) Model the homology search in 3D to understand how broken DNA sites navigate the complex nuclear environment and identify homologous sequences on intricately folded vertebrate sister chromatids. (2) Explore the microscopic mechanisms that drive the large-scale motions and efficient homology search by nucleoprotein filaments. (3) Understand the role of filament-driven homology search in the pairing of homologous chromosomes during meiosis. By integrating these complementary aims, we will build a detailed biophysical, mechanistic picture of homology search. We will calibrate our models against genomic and microscopic datasets, and test their predictions in collaborations with several experimental biology groups. This modeling will provide mechanistic insights into homology search, rigorously test long-standing hypotheses, and generate predictions to guide future experiments. The proposed research will significantly advance our understanding of this key DNA repair process and its potential roles in maintaining genome stability and meiotic recombination.
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| Web resources: | https://cordis.europa.eu/project/id/101163751 |
| Start date: | 01-01-2025 |
| End date: | 31-12-2029 |
| Total budget - Public funding: | 1 500 000,00 Euro - 1 500 000,00 Euro |
Cordis data
Original description
Homology-directed repair is an essential, evolutionary conserved DNA repair pathway that accurately restores genetic information lost due to double-stranded breaks. Its key step is the ‘homology search’, where the broken DNA end locates its matching sequence, typically located on a sister chromatid, to use as a repair template. Despite its significance, the biophysical mechanism of this search within the complex environment of vertebrate genomes remains debated. Emerging hypotheses propose that this search is driven by ‘nucleoprotein’ filaments comprised of repair proteins bound to the broken DNA ends, that actively traverse the nuclear space to find and recognize homologous sequences. We will explore this mechanism by developing quantitative biophysical models that integrate the latest experimental insights on the 3D architecture of sister chromatids and dynamics of nucleoprotein filaments. Our specific aims are: (1) Model the homology search in 3D to understand how broken DNA sites navigate the complex nuclear environment and identify homologous sequences on intricately folded vertebrate sister chromatids. (2) Explore the microscopic mechanisms that drive the large-scale motions and efficient homology search by nucleoprotein filaments. (3) Understand the role of filament-driven homology search in the pairing of homologous chromosomes during meiosis. By integrating these complementary aims, we will build a detailed biophysical, mechanistic picture of homology search. We will calibrate our models against genomic and microscopic datasets, and test their predictions in collaborations with several experimental biology groups. This modeling will provide mechanistic insights into homology search, rigorously test long-standing hypotheses, and generate predictions to guide future experiments. The proposed research will significantly advance our understanding of this key DNA repair process and its potential roles in maintaining genome stability and meiotic recombination.Status
SIGNEDCall topic
ERC-2024-STGUpdate Date
26-11-2024
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