AbstractHomologous recombination during meiosis is critical for chromosome segregation and also gives rise to genetic diversity. Genetic exchange between homologous chromosomes during meiosis is mediated by the recombinase Dmc1, which is capable of recombining DNA sequences with mismatches. The Hop2-Mnd1 complex mediates Dmc1 activity.

减数分裂过程中的同源重组对于染色体分离至关重要，也会产生遗传多样性。减数分裂过程中同源染色体之间的遗传交换是由重组酶Dmc1介导的，该酶能够重组错配的DNA序列。Hop2-Mnd1复合物介导Dmc1活性。

Here, we reveal a regulatory role for Hop2-Mnd1 in restricting substrate selection. Specifically, Hop2-Mnd1 upregulates Dmc1 activity with DNA substrates that are either fully homologous or contain DNA mismatches, and it also acts against DNA strand exchange between substrates solely harboring microhomology.

在这里，我们揭示了Hop2-Mnd1在限制底物选择中的调节作用。具体而言，Hop2-Mnd1用完全同源或含有DNA错配的DNA底物上调Dmc1活性，并且它还对抗仅具有微同源性的底物之间的DNA链交换。

By isolating and examining salient Hop2-Mnd1 separation-of-function variants, we show that suppressing illegitimate DNA recombination requires the Dmc1 filament interaction attributable to Hop2-Mnd1 but not its DNA binding activity. Our study provides mechanistic insights into how Hop2-Mnd1 helps maintain meiotic recombination fidelity..

通过分离和检查显着的Hop2-Mnd1功能分离变体，我们表明抑制非法DNA重组需要可归因于Hop2-Mnd1的Dmc1细丝相互作用，而不是其DNA结合活性。我们的研究提供了关于Hop2-Mnd1如何帮助维持减数分裂重组保真度的机制见解。。

IntroductionThe first meiotic division involves replication, synapsis, and segregation of homologous chromosomes. This process is dependent on the timely execution of homologous recombination (HR) events that occur between each pair of homologous chromosomes. Consequently, HR is a key contributor to generating genetic diversity in the resulting gametes1,2,3.

引言第一次减数分裂涉及同源染色体的复制，突触和分离。这个过程取决于每对同源染色体之间发生的同源重组（HR）事件的及时执行。因此，HR是产生配子遗传多样性的关键因素1,2,3。

Meiotic recombination is initiated via the formation of programmed DNA double-strand breaks (DSBs) introduced by the topoisomerase-like protein Spo114,5. Subsequently, nucleases resect the ends of these DSBs to create 3’ single-stranded DNA (ssDNA) tails6,7 to serve as a template for assembling nucleoprotein filaments by recombinases capable of searching for homology in donor chromosomes, invasion of these latter, and DNA strand exchange between the paired DNA molecules8,9.

减数分裂重组是通过形成由拓扑异构酶样蛋白Spo114,5引入的程序性DNA双链断裂（DSB）来启动的。随后，核酸酶切除这些DSB的末端以产生3'单链DNA（ssDNA）尾部6,7，作为通过重组酶组装核蛋白丝的模板，所述重组酶能够搜索供体染色体中的同源性，入侵这些供体染色体，以及配对DNA分子之间的DNA链交换8,9。

This process results in crossover products that enable cohesion-mediated connection of homologous chromosomes, preparing them for segregation during meiosis.Eukaryotic Rad51 and Dmc1, recombinases that are structurally and functionally related to Escherichia coli RecA protein, help mediate meiotic recombination.

该过程产生交叉产物，使同源染色体的内聚介导的连接成为可能，为减数分裂过程中的分离做好准备。真核生物Rad51和Dmc1是与大肠杆菌RecA蛋白在结构和功能上相关的重组酶，有助于介导减数分裂重组。

Dmc1 expression is restricted to meiosis, whereas Rad51 is also found in mitotic cells10. Studies on the budding yeast Saccharomyces cerevisiae have revealed that Rad51 plays a supporting role in Dmc1-catalyzed recombination during meiosis9,11. Importantly, genetic analysis has demonstrated that Dmc1 can catalyze recombination between highly polymorphic hybrid yeast strains, whereas Rad51 cannot12.

Dmc1表达仅限于减数分裂，而Rad51也存在于有丝分裂细胞中10。对发芽酵母酿酒酵母的研究表明，Rad51在减数分裂过程中在Dmc1催化的重组中起支持作用9,11。重要的是，遗传分析表明，Dmc1可以催化高度多态的杂交酵母菌株之间的重组，而Rad51不能12。

Previous studies using single-molecule and biochemical approaches have corroborated those genetic findings, revealing that Dmc1, but not Rad51, has the capacity to stabilize heteroduplex DNA joints with mismatch-containing base triplets13,14,15.

先前使用单分子和生化方法的研究证实了这些遗传学发现，揭示了Dmc1而非Rad51具有稳定异源双链DNA接头的能力，其中含有错配的碱基三联体13,14,15。

Data availability

数据可用性

All data supporting the findings of this study are available within the paper and its Supplementary Information. Source data are provided with this paper.

本文及其补充信息中提供了支持本研究结果的所有数据。本文提供了源数据。

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Download referencesAcknowledgementsWe thank Dr. Claudia Danilowicz (Harvard University) for valuable help and insightful conversations regarding this study. We extend our gratitude to the Core Facility of the Institute of Biochemical Sciences, National Taiwan University, for their invaluable services.

下载参考文献致谢我们感谢Claudia Danilowicz博士（哈佛大学）对这项研究的宝贵帮助和有见地的对话。我们感谢国立台湾大学生化科学研究所的核心设施，感谢他们提供的宝贵服务。

We appreciate Douglas K. Bishop of The University of Chicago, USA, and Akira Shinohara of Osaka University, Japan, for their generous contributions of the Hop2-Mnd1 and Mei5-Sae3 expression plasmids, respectively. This work was supported by Academia Sinica (P.C.), National Taiwan University (P.C. and H.-W.L.), and the National Science and Technology Council (111-2311-B-002-006-MY3 to P.C., 110-2113-M-002-020 to H.-W.L.).Author informationAuthors and AffiliationsInstitute of Biochemical Sciences, National Taiwan University, Taipei, TaiwanJo-Ching Peng, Hao-Yen Chang & Peter ChiDepartment of Chemistry, National Taiwan University, Taipei, TaiwanHao-Yen Chang, Yuting Liang Sun & Hung-Wen LiDepartment of Physics, Harvard University, Cambridge, MA, 02138, USAMara PrentissInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanPeter ChiAuthorsJo-Ching PengView author publicationsYou can also search for this author in.

我们感谢美国芝加哥大学的Douglas K.Bishop和日本大阪大学的Akira Shinohara分别对Hop2-Mnd1和Mei5-Sae3表达质粒的慷慨贡献。这项工作得到了中央研究院（P.C.），国立台湾大学（P.C.和H.-W.L.）和国家科学技术委员会（111-2311-B-002-006-MY3至P.C.，110-2113-M-002-020至H.-W.L.）的支持。作者信息作者和附属机构国立台湾大学生化科学研究所，台北，台湾大学化学系，台北，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾，台湾。

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PubMed Google ScholarContributionsJ.-C.P. and P.C. conceived the study. J.-C.P., H.-W.L., and P.C. designed the experiments. J.-C.P. performed the majority of protein purifications and biochemical assays. H.-Y.C. and Y.L.S. helped with protein purification and some of the biochemical assays.

PubMed谷歌学术贡献-C、 。J、 -C.P.，H.W.L。和P.C.设计了实验。J、 -C.P.进行了大多数蛋白质纯化和生化分析。H、 -Y.C.和Y.L.S.帮助蛋白质纯化和一些生化测定。

J.-C.P. conducted statistical analyses. J.-C.P. and P.C. wrote the paper with contributions from M.P. All authors engaged in discussions about the results and contributed to the manuscript.Corresponding authorCorrespondence to.

J、 -C.P.进行了统计分析。J、 -C.P.和P.C.在M.P.的贡献下撰写了这篇论文。所有作者都参与了对结果的讨论，并为稿件做出了贡献。对应作者对应。

Peter Chi.Ethics declarations

彼得·奇。道德宣言

Competing interests

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The authors declare no competing interests.

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Nature Communications thanks Hengyao Niu, Patrick Sung and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Nature Communications感谢牛恒尧，宋帕特里克和另一位匿名审稿人对这项工作的同行评审做出的贡献。同行评审文件可用。

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Reprints and permissionsAbout this articleCite this articlePeng, JC., Chang, HY., Sun, Y.L. et al. Hop2-Mnd1 functions as a DNA sequence fidelity switch in Dmc1-mediated DNA recombination.

转载和许可本文引用本文Peng，JC。，Chang，HY.，Sun，Y.L.等人，Hop2-Mnd1在Dmc1介导的DNA重组中起着DNA序列保真度开关的作用。

Nat Commun 15, 9266 (2024). https://doi.org/10.1038/s41467-024-53641-3Download citationReceived: 22 May 2024Accepted: 17 October 2024Published: 27 October 2024DOI: https://doi.org/10.1038/s41467-024-53641-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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