A novel recombination protein C12ORF40/REDIC1 is required for meiotic crossover formation

Cell Discovery

Article

Wasim Shah¹  Baolu Shi¹  Yuanwei Zhang¹  Qinghua Shi¹  Yuewen Wang¹  Xiaohua Jiang¹  Yang Li¹  Zishuo Xu¹  Wei Liu¹  Xuefeng Xie¹  Xiangjun Zhang¹  Muhammad Zubair¹  Hui Ma¹  Yue Wang¹  Huan Zhang¹  Bo Xu¹  Jianteng Zhou¹  Suixing Fan¹  Yuying Jiao¹  Jingwei Ye¹  Hanwei Jiang¹  Zhipeng Xu² 

[1] Division of Reproduction and Genetics, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, University of Science and Technology of China, Hefei, Anhui, China;Institute of Andrology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China;

关键词: ;   

DOI  :  10.1038/s41421-023-00577-5

 received in 2023-01-31, accepted in 2023-06-14,  发布年份 2023

来源: Springer

【 摘 要 】

During meiosis, at least one crossover must occur per homologous chromosome pair to ensure normal progression of meiotic division and accurate chromosome segregation. However, the mechanism of crossover formation is not fully understood. Here, we report a novel recombination protein, C12ORF40/REDIC1, essential for meiotic crossover formation in mammals. A homozygous frameshift mutation in C12orf40 (c.232_233insTT, p.Met78Ilefs*2) was identified in two infertile men with meiotic arrest. Spread mouse spermatocyte fluorescence immunostaining showed that REDIC1 forms discrete foci between the paired regions of homologous chromosomes depending on strand invasion and colocalizes with MSH4 and later with MLH1 at the crossover sites. Redic1 knock-in (KI) mice homozygous for mutation c.232_233insTT are infertile in both sexes due to insufficient crossovers and consequent meiotic arrest, which is also observed in our patients. The foci of MSH4 and TEX11, markers of recombination intermediates, are significantly reduced numerically in the spermatocytes of Redic1 KI mice. More importantly, our biochemical results show that the N-terminus of REDIC1 binds branched DNAs present in recombination intermediates, while the identified mutation impairs this interaction. Thus, our findings reveal a crucial role for C12ORF40/REDIC1 in meiotic crossover formation by stabilizing the recombination intermediates, providing prospective molecular targets for the clinical diagnosis and therapy of infertility.

【 授权许可】

CC BY   
© Center for Excellence in Molecular Cell Science, CAS 2023

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