RAD51AP2 is required for efficient meiotic recombination between X and Y chromosomes

Ma, Hui; Li, Tao; Xie, Xuefeng; Jiang, Long; Ye, Jingwei; Gong, Chenjia; Jiang, Hanwei; Fan, Suixing; Zhang, Huan; Shi, Bingyu; Zhang, Beibei; Jiang, Xiaohua; Li, Yang; Zhou, Jianteng; Xu, Jianze; Zhang, Xingxia; Hou, Xiaoning; Yin, Hong; Zhang, Yuan‐Wei; Shi, Qinghua

doi:10.1126/sciadv.abk1789

Cited by 21 publications

(25 citation statements)

References 62 publications

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“…However, incompletely synapsed autosomes and separated XY chromosomes were observed in pachytene spermatocytes of Redic1 KI mice. Remarkably, in wild-type mice, the autosomes of all pachytene spermatocytes achieved complete synapsis, and 10.62 ± 4.43% of cells exhibited sex chromosome separation, which is consistent with our previous report 8 . However, in Redic1 KI mice, although 12.98% of pachytene spermatocytes presented fully synapsed chromosomes, the remaining 87.12% showed variable synaptic abnormalities.…”

Section: Redic1 Promotes the Assembly Of Synaptonemal Complexessupporting

confidence: 92%

“…Reduction of crossover formation causes not only meiotic arrest in mice but also gametogenesis failure and infertility in humans [2][3][4][5][6] , a complex disease that affects approximately 8%-12% of reproductive-age couples worldwide 7 . Even when the reduction in recombination occurs only between sex chromosomes, apoptosis of spermatocytes and a decreased sperm count will occur, which ultimately affects fertility 8 . Thus, proper crossover formation is crucial for gamete production.…”

Section: Introductionmentioning

confidence: 99%

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

Shi¹,

Fan

Wang³

et al. 2022

Preprint

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During meiosis, at least one crossover must occur in each chromosome pair to ensure their accurate segregation. However, the mechanism of crossover formation is poorly understood. Here, we report a previously uncharacterized recombination protein, C12ORF40/REDIC1, essential for meiotic crossover formation. A homozygous frameshift mutation in C12orf40 was identified in two genetically unrelated infertile men with meiotic arrest. Subsequent analysis showed that REDIC1 forms discrete foci in the paired regions of homologous chromosomes depending on strand invasion. Mouse models mimicking the patients’ mutation showed reductions in crossover and bivalent formation, leading to spermatogenic failure. Notably, mutant spermatocytes displayed reduced numbers of MSH4 and TEX11 foci, accompanied by synaptic defects. Correspondingly, these phenotypes were also observed in our patients. Finally, biochemical results showed that the identified mutation impairs its ability to bind branched recombination intermediates. Therefore, 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.

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Section: Redic1 Promotes the Assembly Of Synaptonemal Complexessupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

Shi¹,

Fan

Wang³

et al. 2022

Preprint

Self Cite

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“…Spermatocyte chromosome spreads and subsequent immunofluorescence staining were performed as previously reported (Jiang et al , 2014; Ma et al , 2022). Information on the antibodies is available in Table EV6.…”

Section: Methodsmentioning

confidence: 99%

M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination

Khan

et al. 2022

EMBO Reports

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Following meiotic recombination, each pair of homologous chromosomes acquires at least one crossover, which ensures accurate chromosome segregation and allows reciprocal exchange of genetic information. Recombination failure often leads to meiotic arrest, impairing fertility, but the molecular basis of recombination remains elusive. Here, we report a homozygous M1AP splicing mutation (c.1074 + 2T > C) in patients with severe oligozoospermia owing to meiotic metaphase I arrest. The mutation abolishes M1AP foci on the chromosome axes, resulting in decreased recombination intermediates and crossovers in male mouse models. M1AP interacts with the mammalian ZZS (an acronym for yeast proteins Zip2‐Zip4‐Spo16) complex components, SHOC1, TEX11, and SPO16. M1AP localizes to chromosomal axes in a SPO16‐dependent manner and colocalizes with TEX11. Ablation of M1AP does not alter SHOC1 localization but reduces the recruitment of TEX11 to recombination intermediates. M1AP shows cytoplasmic localization in fetal oocytes and is dispensable for fertility and crossover formation in female mice. Our study provides the first evidence that M1AP acts as a copartner of the ZZS complex to promote crossover formation and meiotic progression in males.

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“…Recently, researchers have been dedicated to investigating the genealogical tree of male infertility syndromes, including human AZS and TZS by whole-genome sequencing ( Houston et al , 2021 ). Genetic screening has led to the identification of various gene mutations that can cause male infertility both in humans and mice; the mutated genes included FA complementation group M ( FANCM ) ( Yin et al , 2019 ), dynein axonemal heavy chain 17 ( DNAH17 ) ( Zhang et al , 2020 ), Homo sapiens chromosome 14 open reading frame 39 ( C14orf39/SIX6OS1 ) ( Fan et al , 2021 ) and RAD51-associated protein 2 ( RAD51AP2 ) ( Ma et al , 2022 ). In the present work, we focused on illustrating the RNA modification landscape of human sperm to characterize the altered RNA modification signature in AZS and TZS patients.…”

Section: Discussionmentioning

confidence: 99%

Alteration of RNA modification signature in human sperm correlates with sperm motility

Guo

Shen

et al. 2022

Molecular Human Reproduction

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RNA modifications, which are introduced post-transcriptionally, have recently been assigned pivotal roles in the regulation of spermatogenesis and embryonic development. However, the RNA modification landscape in human sperm is poorly characterized, hampering our understanding about the potential role played by RNA modification in sperm. Through our recently developed high-throughput RNA modification detection platform based on liquid chromatography with tandem mass spectroscopy, we are the first to have characterized the RNA modification signature in human sperm. The RNA modification signature was generated on the basis of 49 samples from participants, including 13 healthy controls, 21 patients with asthenozoospermia (AZS) and 15 patients with teratozoospermia (TZS). In total, we identified 13 types of RNA modification marks on the total RNA in sperm, and 16 types of RNA modification marks on sperm RNA fragments of different sizes. The levels of these RNA modifications on the RNA of patients with AZS or TZS were altered, compared to controls, especially on sperm RNA fragments > 80 nt. A few types of RNA modifications, such as m1G, m5C, m2G and m1A, showed clear co-expression patterns as well as high linear correlations with clinical sperm motility. In conclusion, we characterized the RNA modification signature of human sperm and identified its correlation with sperm motility, providing promising candidates for use in clinical sperm quality assessment and new research insights for exploring the underlying pathological mechanisms in human male infertility syndromes.

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RAD51AP2 is required for efficient meiotic recombination between X and Y chromosomes

Abstract: RAD51AP2 is required specifically for efficient meiotic recombination to form crossover between X and Y chromosomes.

Cited by 21 publications

References 62 publications

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

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

M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination

Alteration of RNA modification signature in human sperm correlates with sperm motility

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