A paper published in the journal “Nature Communications” by the Cejka laboratory shows how EXO1, a nuclease known for its role in DNA end resection in homologous recombination and in DNA mismatch repair, has a nuclease-independent role to promote the nuclease activity of MLH1-MLH3 complex.
Bellinzona – May 08 2025 – During meiosis – a specialized cell division that generates eggs and sperm – chromosomes exchange DNA segments through recombination, which promotes genetic variation. The key DNA cleavage activity is carried by the MLH1-MLH3 (MutLγ) complex, which functions together with the MSH4-MSH5 (MutSγ) complex. These proteins are thought to resolve DNA structures called double Holliday junctions to allow proper chromosome segregation. Our research now demonstrates that EXO1 acts as a scaffold, bridging MLH1-MLH3 with MSH4-MSH5 (MutSγ), and DNA itself. Using biochemical and structural modelling approaches, the team found that EXO1 interacts with both MLH1 and MSH4 and the DNA, stabilizing the machinery for proper DNA incision by MutLγ. The work was primarily carried out by Megha Roy and Aurore Sanchez from the Cejka laboratory at the IRB, in collaboration with Raphael Guerois (Université Paris-Saclay), combining expertise in AlphaFold.
