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EXO1 promotes the meiotic MLH1-MLH3 endonuclease through conserved interactions with MLH1, MSH4 and DNA
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EXO1 promotes the meiotic MLH1-MLH3 endonuclease through conserved interactions with MLH1, MSH4 and DNA
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EXO1 promotes the meiotic MLH1-MLH3 endonuclease through conserved interactions with MLH1, MSH4 and DNA
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Journal Article
EXO1 promotes the meiotic MLH1-MLH3 endonuclease through conserved interactions with MLH1, MSH4 and DNA
2025
Overview
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.
EXO1 has a structural role to promote the MLH1-MLH3 nuclease complex to process meiotic recombination intermediates into crossovers. Here, the authors demonstrate that EXO1 function depends on conserved interactions with the MSH4 subunit of MSH4-MSH5, the MLH1 subunit of MLH1-MLH3, and DNA.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/16
/ 82/29
/ 82/83
/ Biochemistry, Molecular Biology
/ DNA
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Exodeoxyribonucleases - chemistry
/ Exodeoxyribonucleases - genetics
/ Exodeoxyribonucleases - metabolism
/ Humanities and Social Sciences
/ Humans
/ Meiosis
/ MutL Protein Homolog 1 - genetics
/ MutL Protein Homolog 1 - metabolism
/ Nuclease
/ Residues
/ Saccharomyces cerevisiae - genetics
/ Saccharomyces cerevisiae - metabolism
/ Saccharomyces cerevisiae Proteins - genetics
/ Saccharomyces cerevisiae Proteins - metabolism
/ Science
/ Yeast
