An essential role of the E3 ubiquitin ligase RNF126 in ensuring meiosis I completion during spermatogenesis,Journal of Advanced Research

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An essential role of the E3 ubiquitin ligase RNF126 in ensuring meiosis I completion during spermatogenesis
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-08-12 , DOI: 10.1016/j.jare.2024.08.011
Wenjing Liu ₁ , Xiya Sun ₂ , Fubing Li ₃ , Qiuyun Jiang ₄ , Jianting An ₅ , Yingying Wu ₆ , Jingyi Yang ₅ , Meng Qin ₂ , Yuxin Zhao ₇ , Yongjia Tang ₈ , Tingyue Wu ₄ , Zhiqiang Yan ₂ , Dewei Jiang ₄ , Rong Liu ₄ , Wenhui Li ₇ , Xu Zhi ₂ , Ceshi Chen ₉

Affiliation

The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China; Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China.
State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China.
Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China.
Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China.
State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Department of the Pathology, First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.
The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China.
Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310063, China.
The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China; Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China.

Introduction

Homologous recombination repair during meiosis is essential for the exchange of genetic information between sister chromosomes, underpinning spermatogenesis and, consequently, fertility. The disruption of this process can lead to infertility, highlighting the importance of identifying the molecular actors involved.

Objectives

This study aims to elucidate the role of the E3 ubiquitin ligase Rnf126 in spermatogenesis and its impact on fertility, particularly through its involvement in meiotic homologous recombination repair.

Methods

We used heterozygous and homozygous Rnf126 deletion models in mouse testes to examine the consequences on testicular health, sperm count, and the process of spermatogenesis. Additionally, we explored the association between RNF126 gene missense variants and nonobstructive male infertility in patients, with a focus on their functional impact on the protein’s ubiquitin ligase activity.

Results

Rnf126 deletion led to testicular atrophy, disrupted seminiferous tubule structure, reduced sperm count, and spermatogenesis arrest at meiotic prophase I. Furthermore, male mice exhibited impaired homologous recombination repair and increased apoptosis within the seminiferous tubules. We identified four missense variants of the RNF126 (V68M, R241H, E261A, D253N) associated with male infertility. Specifically, the E261A and D253N variants, located in the RING domain, directly compromised the E3 ubiquitin ligase activity of RNF126.

Conclusion

Our findings demonstrate the pivotal role of RNF126 in maintaining spermatogenesis and fertility, offering insights into the molecular mechanisms underlying male infertility. The identified RNF126 variants present novel targets for diagnostic and therapeutic strategies in treating nonobstructive male infertility.

中文翻译：

E3 泛素连接酶 RNF126 在确保精子发生过程中减数分裂 I 完成中的重要作用

介绍

减数分裂期间的同源重组修复对于姐妹染色体之间的遗传信息交换至关重要，是精子发生的基础，因此是生育的基础。这个过程的破坏会导致不孕症，这凸显了确定所涉及的分子行为者的重要性。

目标

本研究旨在阐明 E3 泛素连接酶 Rnf126 在精子发生中的作用及其对生育能力的影响，特别是通过其参与减数分裂同源重组修复。

方法

我们在小鼠睾丸中使用杂合和纯合 Rnf126 缺失模型来检查对睾丸健康、精子数量和精子发生过程的影响。此外，我们探讨了 RNF126 基因错义变异与患者非梗阻性男性不育症之间的关联，重点关注它们对蛋白质泛素连接酶活性的功能影响。

结果

RNF126 缺失导致睾丸萎缩、生精小管结构破坏、精子数量减少和减数分裂前期 I 的精子发生停滞。此外，雄性小鼠表现出同源重组修复受损和生精小管内细胞凋亡增加。我们确定了与男性不育相关的 RNF126 的 4 个错义变异（V68M 、 R241H 、 E261A 、 D253N）。具体来说，位于 RING 结构域的 E261A 和 D253N 变体直接损害了 RNF126 的 E3 泛素连接酶活性。