Alternative titles; symbols
HGNC Approved Gene Symbol: SPO11
Cytogenetic location: 20q13.31 Genomic coordinates (GRCh38) : 20:57,329,803-57,343,993 (from NCBI)
Meiotic recombination is initiated by programmed DNA double-strand breaks at the beginning of meiotic prophase. SPO11-beta is the catalytic subunit of a DNA topoisomerase VI-like protein complex that is indispensable for meiotic recombination (Robert et al., 2016).
In yeast, SPO11 is required for meiotic DSB formation and is covalently linked to the 5-prime end of DSBs during meiosis. Using oligonucleotides from an EST with similarity to the Drosophila Spo11 homolog, Romanienko and Camerini-Otero (1999) designed PCR primers to clone Spo11 from a mouse testis cDNA library. They used mouse Spo11 to clone the human homolog, which encodes a deduced 396-amino acid protein. In both the human and mouse proteins, region I contains the putative active site tyrosine, and regions II, III, and IV comprise a Toprim (topoisomerase and primase) domain including an invariant glutamate residue in region II and a DXD motif in region IV. Toprim domains are conserved in many proteins involved in DNA replication and repair. The human and the mouse SPO11 proteins share 82% amino acid identity, but only 20 to 30% with other eukaryotic homologs such as Drosophila and C. elegans. Both the mouse and human SPO11 exons 2 and 8 are subject to alternative splicing. Northern blot analysis showed that mouse Spo11 is expressed in testis and thymus as a 1.8-kb mRNA, whereas human SPO11 is expressed in testis as a 2.0-kb transcript. RT-PCR revealed that human SPO11 is also expressed in prostate, fetal testis, thymus, and some carcinoma cell lines. Shannon et al. (1999) independently cloned mouse and human SPO11 cDNAs and demonstrated that mouse Spo11 is expressed only in testicular germ cells, specifically in juvenile pachytene spermatocytes and mid-to-late pachytene spermatocytes.
Robert et al. (2016) stated that 2 isoforms of mouse Spo11, alpha and beta, contain 358 and 396 amino acids, respectively, and they differ by exclusion or inclusion of a 38-residue sequence near the N terminus.
Tsubouchi and Roeder (2005) described a process in meiotic cells of budding yeast in which chromosomes become joined together in pairs at their centromeres independent of chromosomal homology. The centromeric interactions depend on the synaptonemal complex component Zip1. During meiosis in wildtype diploids, centromere couples are initially nonhomologous and then undergo switching until all couples involve homologs. This transition to homologous coupling depends on Spo11, a protein required for the initiation of meiotic recombination. Regions of synaptonemal complex assembled early in meiosis are often centromere-associated. Tsubouchi and Roeder (2005) proposed that centromere coupling facilitates homolog pairing and promotes synapsis initiation.
Neale et al. (2005) showed that meiotic DSBs in budding yeast are processed by endonucleolytic cleavage that releases Spo11 attached to an oligonucleotide with a free 3-prime hydroxyl.
Guillon et al. (2005) analyzed crossovers and noncrossovers in oogenesis and spermatogenesis in mice and determined that both crossover and noncrossover pathways were Spo11 dependent. Mlh1 (120436) was required for the formation of most crossovers, but not noncrossovers.
Using genetic reporters as proxies to follow in vivo activation of the p53 (191170) network in Drosophila, Lu et al. (2010) discovered that the process of meiotic recombination instigates programmed activation of p53 in the germline. Specifically, double-stranded breaks in DNA generated by the topoisomerase Spo11 provoked functional p53 activity, which was prolonged in cells defective for meiotic DNA repair. This intrinsic stimulus for the p53 regulatory network is highly conserved, as Spo11-dependent activation of p53 also occurs in mice. Lu et al. (2010) concluded that their findings established a physiologic role for p53 in meiosis and suggested that tumor-suppressive functions may have been co-opted from primordial activities linked to recombination.
Kauppi et al. (2011) found that mouse pseudoautosomal region (PAR) DNA occupies unusually long chromosome axes, potentially as shorter chromatin loops, predicted to promote double-strand break (DSB) formation. Most PARs undergo delayed appearance of RAD51 (179617)/DMC1 (602721) foci, which mark DSB ends, and all PARs undergo delayed DSB-mediated homologous pairing. Analysis of Spo11-beta isoform-specific transgenic mice revealed that RAD51/DMC1 foci in the PAR are genetically distinct from both early PAR foci and global foci and that late PAR foci promote efficient X-Y pairing, recombination, and male fertility. Kauppi et al. (2011) concluded that their findings uncovered specific mechanisms that surmount the unique challenges of X-Y recombination.
Lange et al. (2011) reported that the number of meiotic double-strand breaks in mouse is controlled by Atm (607585). Levels of Spo11-oligonucleotide complexes, byproducts of meiotic double-strand break formation, are elevated at least 10-fold in spermatocytes lacking Atm. Moreover, Atm mutation renders Spo11-oligonucleotide levels sensitive to genetic manipulations that modulate Spo11 protein levels. Lange et al. (2011) proposed that ATM restrains SPO11 via a negative feedback loop in which kinase activation by double-strand breaks suppresses further double-strand break formation. Lange et al. (2011) concluded that their findings explained previously puzzling phenotypes of Atm-null mice and provided a molecular basis for the gonadal dysgenesis observed in ataxia telangiectasia (208900).
Garcia et al. (2011) used Saccharomyces cerevisiae to reveal a role for the Mre11 (600814) exonuclease during the resection of Spo11-linked 5-prime DNA termini in vivo. They showed that the residual resection observed in Exo1 (606063)-mutant cells is dependent on Mre11, and that both exonuclease activities are required for efficient double-strand break repair. Previous work had indicated that resection traverses unidirectionally. Using a combination of physical assays for 5-prime-end processing, Garcia et al. (2011) observed results indicating an alternative mechanism involving bidirectional resection. First, Mre11 nicks the strand to be resected up to 300 nucleotides from the 5-prime terminus of the double-strand break, much further away than previously assumed. Second, this nick enables resection in a bidirectional manner, using Exo1 in the 5-prime-to-3-prime direction away from the double-strand break, and Mre11 in the 3-prime-to-5-prime direction towards the double-strand break end. Mre11 exonuclease activity also confers resistance to DNA damage in cycling cells, suggesting that Mre11-catalyzed resection may be a general feature of various DNA repair pathways.
Robert et al. (2016) determined that mouse Spo11-beta, but not Spo11-alpha, interacts with Topovibl (C11ORF80; 616109) in a heterodimer or heterotetramer of between 150 to 250 kD. In mice, expression of a Topovibl protein lacking the C-terminal transducer domain resulted in male and female sterility, with germ cell failure during meiotic prophase. Robert et al. (2016) concluded that meiotic double-strand breaks require a complex made up of both Spo11 and Topovibl.
By FISH, Romanienko and Camerini-Otero (1999) mapped the mouse Spo11 gene near the telomere on chromosome 2H4 and the human SPO11 gene in a region of syntenic homology on 20q13.2-q13.3. This region of chromosome 20 is known to be amplified in breast and ovarian cancer and, when amplified, correlates with increased genomic instability in human papillomavirus-transformed cell lines.
Romanienko and Camerini-Otero (2000) generated mice with targeted disruption of the Spo11 gene. Homozygosity for this disruption resulted in infertility. Spermatocytes arrested prior to pachytene with little or no synapsis and underwent apoptosis. Rad51 (179617) and Dmc1 (602721) foci in meiotic chromosome spreads were not detected, indicating that DSBs were not formed. Cisplatin-induced DSBs restored Rad51 and Dmc1 foci and promoted synapsis. Spo11 localized to discrete foci during leptotene and to homologously synapsed chromosomes. Other mouse mutants that arrest during meiotic prophase (Atm (607585) -/-, Dmc1 -/-, Mei1 (608797) -/-, and Morc (603205) -/-) showed altered Spo11 protein localization and expression. The authors speculated that there is an additional role for Spo11, after it generates DSBs, in synapsis.
Baudat et al. (2000) reported that disruption of mouse Spo11 led to severe gonadal abnormalities from defective meiosis. Spermatocytes suffered apoptotic death during early prophase. Oocytes reached the diplotene/dictyate stage in nearly normal numbers, but most died soon after birth. Consistent with a conserved function in initiating meiotic recombination, Dmc1 and Rad51 foci formation was abolished. Spo11 -/- meiocytes also displayed homologous chromosome synapsis defects, similar to fungi but distinct from flies and nematodes. The authors proposed that recombination initiation precedes and is required for normal synapsis in mammals. Their results also supported the view that mammalian checkpoint responses to meiotic recombination and/or synapsis defects are sexually dimorphic.
Baudat, F., Manova, K., Yuen, J. P., Jasin, M., Keeney, S. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Molec. Cell 6: 989-998, 2000. [PubMed: 11106739] [Full Text: https://doi.org/10.1016/s1097-2765(00)00098-8]
Garcia, V., Phelps, S. E. L., Gray, S., Neale, M. J. Bidirectional resection of DNA double-strand breaks by Mre11 and Exo1. Nature 479: 241-244, 2011. [PubMed: 22002605] [Full Text: https://doi.org/10.1038/nature10515]
Guillon, H., Baudat, F., Grey, C., Liskay, R. M., de Massy, B. Crossover and noncrossover pathways in mouse meiosis. Molec. Cell 20: 563-573, 2005. [PubMed: 16307920] [Full Text: https://doi.org/10.1016/j.molcel.2005.09.021]
Kauppi, L., Barchi, M., Baudat, F., Romanienko, P. J., Keeney, S., Jasin, M. Distinct properties of the XY pseudoautosomal region crucial for male meiosis. Science 331: 916-920, 2011. [PubMed: 21330546] [Full Text: https://doi.org/10.1126/science.1195774]
Lange, J., Pan, J., Cole, F., Thelen, M. P., Jasin, M., Keeney, S. ATM controls meiotic double-strand-break formation. Nature 479: 237-240, 2011. [PubMed: 22002603] [Full Text: https://doi.org/10.1038/nature10508]
Lu, W.-J., Chapo, J., Roig, I., Abrams, J. M. Meiotic recombination provokes functional activation of the p53 regulatory network. Science 328: 1278-1281, 2010. [PubMed: 20522776] [Full Text: https://doi.org/10.1126/science.1185640]
Neale, M. J., Pan, J., Keeney, S. Endonucleolytic processing of covalent protein-linked DNA double-strand breaks. (Letter) Nature 436: 1053-1057, 2005. [PubMed: 16107854] [Full Text: https://doi.org/10.1038/nature03872]
Robert, T., Nore, A., Brun, C., Maffre, C., Crimi, B., Guichard, V., Bourbon, H.-M., de Massy, B. The TopoVIB-like protein family is required for meiotic DNA double-strand break formation. Science 351: 943-949, 2016. Note: Erratum: Science 352: May 6, 2016. [PubMed: 26917764] [Full Text: https://doi.org/10.1126/science.aad5309]
Romanienko, P. J., Camerini-Otero, R. D. Cloning, characterization, and localization of mouse and human SPO11. Genomics 61: 156-169, 1999. [PubMed: 10534401] [Full Text: https://doi.org/10.1006/geno.1999.5955]
Romanienko, P. J., Camerini-Otero, R. D. The mouse Spo11 gene is required for meiotic chromosome synapsis. Molec. Cell 6: 975-987, 2000. [PubMed: 11106738] [Full Text: https://doi.org/10.1016/s1097-2765(00)00097-6]
Shannon, M., Richardson, L., Christian, A., Handel, M. A., Thelen, M. P. Differential gene expression of mammalian SPO11/TOP6A homologs during meiosis. FEBS Lett. 462: 329-334, 1999. [PubMed: 10622720] [Full Text: https://doi.org/10.1016/s0014-5793(99)01546-x]
Tsubouchi, T., Roeder, G. S. A synaptonemal complex protein promotes homology-independent centromere coupling. Science 308: 870-873, 2005. [PubMed: 15879219] [Full Text: https://doi.org/10.1126/science.1108283]