Project information
Mechanics and execution of homologous recombination - biophysics to the organism
- Project Identification
- 206292/E/17/Z
- Project Period
- 6/2018 - 12/2023
- Investor / Pogramme / Project type
-
Wellcome Trust
- Wellcome Trust Projects
- MU Faculty or unit
- Faculty of Medicine
- Cooperating Organization
-
Columbia University
- Responsible person Prof. Eric Greene
- Responsible person Prof. David Rueda
- Responsible person Dr. Simon Boulton
Homologous recombination (HR) is an essential mechanism for the repair of DNA double-strand breaks and damaged replication forks and is associated with genetic disorders, cancer and aging. HR repairs DNA damage by copying the correct genetic information from an intact chromosomal template, which is critically dependent on the recombinase RAD51. To ensure its timely and accurate completion, HR is positively and negatively regulated by RAD51 co-factors and antiPage recombinases. How these HR regulators function at the molecular level remains poorly understood and represents a significant challenge to the field due to the lack of mechanistic resolution afforded by conventional bulk biochemical approaches. We recently pioneered several cutting-edge biophysical approaches to interrogate the HR reaction in unprecedented detail.
Importantly, we demonstrated the power of integrating data from these complementary methodologies to uncover the mechanism of action of the Rad51 paralogs in modulating RAD51 to promote HR. The aim of our proposal is to extend this paradigm to study multiple different HR regulators to gain insights into how they work individually and how they act cooperatively during HR. Deciphering how HR regulators work will provide an improved understanding of the molecular mechanisms relevant to carcinogenesis and may present unique opportunities for therapeutic intervention.
Sustainable Development Goals
Masaryk University is committed to the UN Sustainable Development Goals, which aim to improve the conditions and quality of life on our planet by 2030.
Publications
Total number of publications: 12
2024
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Physical interaction with Spo11 mediates the localisation of Mre11 to chromatin in meiosis and promotes its nuclease activity
Nucleic acids research, year: 2024, DOI
2023
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MUS81 cleaves TOP1‑derived lesions and other DNA-protein cross‑links
BMC Biology, year: 2023, volume: 21, edition: 1, DOI
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Recognition and coacervation of G-quadruplexes by a multifunctional disordered region in RECQ4 helicase
Nature Communications, year: 2023, volume: 14, edition: 1, DOI
2022
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The role of bivalent ions in the regulation of D-loop extension mediated by DMC1 during meiotic recombination
iSCIENCE, year: 2022, volume: 25, edition: 11, DOI
2021
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In Vitro Characterization of Sumoylation of HR Proteins
Homologous Recombination: Methods and Protocols, year: 2021, number of pages: 20 s.
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Nucleotide proofreading functions by nematode RAD51 paralogs facilitate optimal RAD51 filament function
Nature Communications, year: 2021, volume: 12, edition: 1, DOI
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Single-molecule visualization of human RECQ5 interactions with single-stranded DNA recombination intermediates
Nucleic acids research, year: 2021, volume: 49, edition: 1, DOI
2020
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DSS1 interacts with and stimulates RAD52 to promote the repair of DSBs
Nucleic Acids Research, year: 2020, volume: 48, edition: 2, DOI
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RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops
Nature, year: 2020, volume: 587, edition: 7833, DOI
2019
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Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome
CLINICAL EPIGENETICS, year: 2019, volume: 11, edition: 1, DOI