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Genetics of mammalian meiosis
Published in C. Yan Cheng, Spermatogenesis, 2018
Meiotic recombination begins with the formation of DNA double-strand breaks (DSBs). In mouse, about 300 DSBs are generated in each meiotic germ cell. Formation of DSBs is catalyzed by SPO11, a homologue of TopoVI DNA topoisomerase subunit A (TopoVIA).55–57 The activity of SPO11 requires TOPOVIBL, which displays structural similarity to the TopoVI DNA topoisomerase subunit B.58 TOPOVIBL interacts with SPO11 and is required for DSB formation during meiosis. Additional proteins are required for DSB formation: MEI1,59 MEI4,60 REC114,60 HORMAD1,61,62 and IHO1.63 MEI4 and REC114 interact directly.60 HORMAD1 localizes to unsynapsed chromosomal axis and recruits IHO1 through direct interaction. IHO1 recruits MEI4-REC114 to unsynapsed chromosomal axis. The formation of this complex (HORMAD1-IHO1-REC114-MEI4) activates the SPO11-TOPOVIBL complex.63 MEI1 is also important for recruitment of MEI4.64 In conclusion, meiotic DSB formation is genetically programmed and meticulously executed (Figure 8.1).
Sperm chromatin assessment
Published in David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham, Textbook of Assisted Reproductive Techniques, 2017
Ashok Agarwal, Rakesh Sharma, Gulfam Ahmad
Meiotic crossing-over is associated with the genetically programmed introduction of DNA double-strand breaks (DSBs) by specific nucleases of the SPO11 family (88). These DNA DSBs should be ligated until the end of meiosis I. Normally, a recombination checkpoint in meiotic prophase does not allow meiotic division I to proceed until DNA is fully repaired or defective spermatocytes are ablated (88, 89). A defective checkpoint may lead to persistent sperm DNA fragmentation in ejaculated spermatozoa, although direct data for this hypothesis in humans is lacking.
Genetic variations as molecular diagnostic factors for idiopathic male infertility: current knowledge and future perspectives
Published in Expert Review of Molecular Diagnostics, 2021
Mohammad Karimian, Leila Parvaresh, Mohaddeseh Behjati
C631T polymorphism with replacement of Arg211Trp in peptide sequence is associated with altered secondary structure of SPO11 as well as changed structure of the coils, strands, and helices. The mutation also results in altered physicochemical properties of SPO11 protein. Thus, the molecular weight (MW) of normal SPO11 protein is lower than that of protein with phenotype 631T. Also, in the natural protein, the total number of negative residues (Asp and Glu) is 41 and the total number of positive residues (Arg and Lys) is 50, while this value in the mutant protein is 41 and 49, respectively. Therefore, PI changes from 9.05 for the normal protein to 8.97 in the SPO11 mutation. As a result, the ratio of PI to MW for the mutant protein increases [79]. Our previous study showed that C631T transcription did not affect the binding affinity of chaperones and amyloid-forming regions while enhancing aggregation of prone regions in SPO11 protein. Predicting the impact of C631T on secondary RNA structure in SPO11 revealed that this SNP induced fundamental changes in the secondary mRNA structure [79]. All of these data could explain the pathogenicity of C631T mutation on male infertility.
Long-term exposure to formaldehyde induced down-regulation of SPO11 in rats
Published in Inhalation Toxicology, 2021
Pan Ge, Xiang Zhang, Yan-qi Yang, Mo-qi Lv, Dang-xia Zhou
Spermatogenesis involves highly complex physiological processes, especially meiosis (Griswold 2016). When adverse environmental factors interfere or genetic materials are disturbed, the normal spermatogenic process, particularly meiosis, may be affected, leading to the development of spermatogenic disorders. Meiosis is an essential part of spermatogenesis, and the SPO11 gene is one of the important genes involved in meiosis. SPO11, a meiosis-related gene, is a type II topoisomerase, which mediates DNA DSBs to trigger chromosomal breaks in meiotic recombination and promote pairing with synaptonemal complex formation between homologous chromosomes (Bloomfield 2016). Smirnova et al. reported that SPO11-/-mice could not complete chromosome synapsis and chromosome condensation, resulting in abnormal spermatogenesis (Smirnova et al. 2006). Moreover, the study of Ren et al. showed that the SPO11 gene C631T polymorphism might be a susceptible genetic factor leading to male infertility (Ren et al. 2017).