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EXO1通过与MLH1、MSH4和DNA的保守相互作用促进减数分裂MLH1-MLH3核酸内切酶的活性。

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

作者信息

Roy Megha, Sanchez Aurore, Guerois Raphael, Senoussi Issam, Cerana Arianna, Sgrignani Jacopo, Cavalli Andrea, Rinaldi Andrea, Cejka Petr

机构信息

Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland.

Institut Curie, PSL University, Sorbonne Université, CNRS UMR3244, Paris, France.

出版信息

Nat Commun. 2025 May 3;16(1):4141. doi: 10.1038/s41467-025-59470-2.

DOI:10.1038/s41467-025-59470-2
PMID:40319035
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12049449/
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.

摘要

MLH1-MLH3（MutLγ）的核酸内切酶活性受到MSH4-MSH5（MutSγ）、EXO1和RFC-PCNA的刺激，以将减数分裂重组中间体（如双Holliday连接体（HJs））解析为交叉互换。我们发现，EXO1通过EXO1的MIP基序和围绕EXO1-I403的一个区域直接与MLH1相互作用。意外的是，破坏这种相互作用仅部分抑制了MutLγ。我们还发现，EXO1也直接与MutSγ相互作用。至关重要的是，EXO1中的单点突变（W371E）损害了其与MSH4的相互作用，并完全消除了其激活MutLγ进行DNA切口的能力，而不影响其内在的核酸酶功能。最后，破坏EXO1核酸酶结构域中的镁配位残基对MutSγ-MutLγ活性没有影响，而介导与双链DNA（dsDNA）相互作用的EXO1残基的完整性很重要。我们的研究结果表明，EXO1是减数分裂解离酶复合物不可或缺的结构成分，这得到了其与MutSγ、MutLγ和dsDNA保守相互作用的支持。我们提出，EXO1有助于将MutSγ-MutLγ拴系到HJ识别下游的dsDNA上，以促进DNA切割。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/cc515f14fc27/41467_2025_59470_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/0e71a46af259/41467_2025_59470_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/4b5977675e50/41467_2025_59470_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/8754ed62642a/41467_2025_59470_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/70cefde3722f/41467_2025_59470_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/35af1daf5912/41467_2025_59470_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/68584d7830b9/41467_2025_59470_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/cc515f14fc27/41467_2025_59470_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/0e71a46af259/41467_2025_59470_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/4b5977675e50/41467_2025_59470_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/8754ed62642a/41467_2025_59470_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/70cefde3722f/41467_2025_59470_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/35af1daf5912/41467_2025_59470_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/68584d7830b9/41467_2025_59470_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b04/12049449/cc515f14fc27/41467_2025_59470_Fig7_HTML.jpg

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本文引用的文献

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Nat Commun. 2025 Apr 16;16(1):3613. doi: 10.1038/s41467-025-57928-x.
2
From interaction networks to interfaces, scanning intrinsically disordered regions using AlphaFold2.从相互作用网络到界面，使用 AlphaFold2 扫描无序区域。
Nat Commun. 2024 Jan 18;15(1):597. doi: 10.1038/s41467-023-44288-7.
3
Genetic dissection of crossover mutants defines discrete intermediates in mouse meiosis.
遗传剖析交叉突变体定义了小鼠减数分裂中的离散中间产物。
Mol Cell. 2023 Aug 17;83(16):2941-2958.e7. doi: 10.1016/j.molcel.2023.07.022.
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Exo1 protects DNA nicks from ligation to promote crossover formation during meiosis.Exo1 保护 DNA 切口免受连接，以促进减数分裂过程中的交叉形成。
PLoS Biol. 2023 Apr 20;21(4):e3002085. doi: 10.1371/journal.pbio.3002085. eCollection 2023 Apr.
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MobiDB: 10 years of intrinsically disordered proteins.MobiDB：10 年的无序蛋白质。
Nucleic Acids Res. 2023 Jan 6;51(D1):D438-D444. doi: 10.1093/nar/gkac1065.
6
Role of EXO1 nuclease activity in genome maintenance, the immune response and tumor suppression in Exo1D173A mice.EXO1 核酸酶活性在基因组维持、免疫反应和 Exo1D173A 小鼠肿瘤抑制中的作用。
Nucleic Acids Res. 2022 Aug 12;50(14):8093-8106. doi: 10.1093/nar/gkac616.
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Nat Methods. 2022 Jun;19(6):679-682. doi: 10.1038/s41592-022-01488-1. Epub 2022 May 30.
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