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Unveiling Rad52: a key player in homologous recombination


​​​​​​Researchers from IRCM, in collaboration with Institut Curie, CNRS, Université Paris-Saclay and the synchrotron Soleil, have identified a C-terminal segment of the Rad52 protein that plays an essential chaperone role in the formation and stabilization of Rad51 filaments, which are crucial for DNA repair through homologous recombination.

These findings were published in July 2025 in Nature Communications.

Published on 1 July 2025

​Homologous recombination is a key mechanism for repairing DNA, particularly double-strand breaks, and relies on the formation of Rad51 protein filaments on single-stranded DNA. These filaments enable the search for an intact DNA molecule carrying sequences identical to the damaged DNA and promote copying of that sequence—central steps in the repair process. The Rad52 protein plays a critical role in this mechanism in the yeast Saccharomyces cerevisiae, but the molecular basis of its action has remained poorly understood.

In this work published by a team at IRCM, the researchers identified a key region of Rad52: an 85–amino acid segment located in its C-terminal part, conserved across fungi. Using integrative approaches (NMR, SAXS, AlphaFold modeling, targeted mutagenesis, and in vivo assays), they showed that this segment folds specifically upon binding to a broad surface of a Rad51 monomer. This interaction includes an FxxA motif also found in the BRC repeats of BRCA2, the functional Rad51 mediator in mammals.

The results demonstrate that:

  • this Rad52 segment prevents the spontaneous oligomerization of Rad51 and promotes the formation of a soluble Rad51–Rad52 complex in a 1:1 ratio;

  • it acts as an “assembly chaperone,” solubilizing Rad51 in its monomeric form and facilitating the nucleation and elongation of functional filaments on single-stranded DNA;

  • it protects these filaments against the action of Srs2, a helicase that normally destabilizes them;

  • point mutations in three “anchoring” residues (F316, F337, Y376) abolish this interaction, resulting in strong sensitivity to DNA-damaging agents (alkylating agents, γ-rays) and a drastic reduction in Rad51 recruitment to DNA breaks.

 

These observations show that Rad52 does more than acting as a classical mediator: it functions as a genuine molecular chaperone, essential for the formation and stability of Rad51 filaments. The study also highlights parallels with BRCA2 in humans, strengthening the idea that analogous mechanisms exist to safeguard homologous recombination across species.

​Contact : eric.coic@cea.fr​ ​

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