EXO1 promotes the meiotic MLH1-MLH3 endonuclease through conserved interactions with MLH1, MSH4 and DNA

Megha Roy, Aurore Sanchez (), Raphael Guerois, Issam Senoussi, Arianna Cerana, Jacopo Sgrignani, Andrea Cavalli, Andrea Rinaldi and Petr Cejka ()
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Megha Roy: Faculty of Biomedical Sciences
Aurore Sanchez: Faculty of Biomedical Sciences
Raphael Guerois: Institute for Integrative Biology of the Cell (I2BC)
Issam Senoussi: Faculty of Biomedical Sciences
Arianna Cerana: Faculty of Biomedical Sciences
Jacopo Sgrignani: Faculty of Biomedical Sciences
Andrea Cavalli: Faculty of Biomedical Sciences
Andrea Rinaldi: Faculty of Biomedical Sciences
Petr Cejka: Faculty of Biomedical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The endonuclease activity of MLH1-MLH3 (MutLγ) is stimulated by MSH4-MSH5 (MutSγ), EXO1, and RFC-PCNA to resolve meiotic recombination intermediates such as double Holliday junctions (HJs) into crossovers. We show that EXO1 directly interacts with MLH1 via the EXO1 MIP motif and a patch centered around EXO1-I403. Disrupting this interaction unexpectedly only partially inhibited MutLγ. We found that EXO1 also directly interacts with MutSγ. Crucially, a single point mutation in EXO1 (W371E) impairs its interaction with MSH4 and completely abolished its ability to activate DNA nicking by MutLγ without affecting its intrinsic nuclease function. Finally, disrupting magnesium coordinating residues in the nuclease domain of EXO1 has no impact on MutSγ-MutLγ activity, while the integrity of EXO1 residues mediating interactions with double-stranded DNA (dsDNA) is important. Our findings suggest EXO1 is an integral structural component of the meiotic resolvase complex, supported by conserved interactions with MutSγ, MutLγ and dsDNA. We propose that EXO1 helps tether MutSγ-MutLγ to dsDNA downstream of HJ recognition to promote DNA cleavage.

Date: 2025
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DOI: 10.1038/s41467-025-59470-2

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