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Laboratory of Genetic and Molecular Radiobiology - LRGM

UMR SGCSR - U1274

Published on 15 February 2019
LRGM.png Electron microscopy images of protein-DNA complexes showing the association of Rad52 with complete Rad51 filaments.
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Eric COIC
Principal investigator
Tél : +33 (0)1 46 54 90 53​
eric.coic@cea.fr

 

​Regulation of Rad51 nucleoprotein filament formation and Genomic stability​

The association of Homologous recombination (HR) defects with numerous genetic diseases highlights the critical role of HR in maintaining genome stability. A key step in HR is the formation of Rad51 filaments that can perform homology search. We found that Rad51 filaments are subject to a tight regulation to avoid unproductive entities that can lead to cell death (Esta et al., PloS Genet, 2013). Mediator proteins, such as hBRCA2 in humans or yRad52 in the yeast Saccharomyces cerevisiae, drive Rad51 filament formation together with Rad51 paralogue proteins (like yRad55/yRad57) that prevent displacement of Rad51 filaments by several DNA helicases (hBLM, ySrs2…). ySrs2 is known to remove toxic Rad51 filaments, the nature of which is still not defined. In humans, most of these helicases are tumor suppressors, illustrating the importance of Rad51 filament regulation. Details of this regulation as well as the nature of toxic Rad51 filaments are far being understood. We are conducting genetics and biochemical experiments to describe precisely the nature of this regulation in the yeast Saccharomyces cerevisiae.​

Projects
  • Genetic and molecular analysis of mediator activity. How do mediators displace RPA and how do they assemble rad51 protein filaments?
  • What does distinguish a proper Rad51 filament engaged in HR, protected from helicases activity, from a toxic one, substrate of helicases?
  • What is the basis of Rad51 filaments potential toxicity? We are planning to isolate toxic rad51 filaments in vivo in order to determine which cellular mecanisms is affected by their formation (DNA replication, DNA repair, late steps of HR…).
  • Search for other proteins involved in Rad51 filament formation.
Technics used
  • Yeast genetics.
  • Molecular biology (ChIP, co-IP…).
  • Protein biochemistry (protein purification, in vitro analysis of nucleoproteic complexes).
  • Electronic microscopy analysis of nucleoproteic complexes​ (in collaboration with Eric Le Cam, IGR, Villejuif)​.

Collaborations
Françoise OCHSENBEIN, CEA-CNRS-Université Paris-Sud/I2BC/Bât 144, Gif-Sur-Yvette.
Raphaël GUE​​​ROISCEA-CNRS-Université Paris-Sud/I2BC/Bât 144, Gif-Sur-Yvette.
Eric LE CAM, IGR,Villejuif.


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