Abstract
Recombination is crucial for chromosome pairing and segregation during meiosis. SPATA22, along with its direct binding partner and functional collaborator, MEIOB, is essential for the proper repair of double-strand breaks (DSBs) during meiotic recombination. Here, we describe a novel point-mutated allele (shani) of mouse Spata22 that we isolated in a forward genetic screen. shani mutant mice phenocopy Spata22-null and Meiob-null mice: mutant cells appear to form DSBs and initiate meiotic recombination, but are unable to complete DSB repair, leading to meiotic prophase arrest, apoptosis and sterility. shani mutants show precocious loss of DMC1 foci and improper accumulation of BLM-positive recombination foci, reinforcing the requirement of SPATA22-MEIOB for the proper progression of meiotic recombination events. The shani mutation lies within a Spata22 coding exon and molecular characterization shows that it leads to incorrect splicing of the Spata22 mRNA, ultimately resulting in no detectable SPATA22 protein. We propose that the shani mutation alters an exonic splicing enhancer element (ESE) within the Spata22 transcript. The affected DNA nucleotide is conserved in most tetrapods examined, suggesting that the splicing regulation we describe here may be a conserved feature of Spata22 regulation.
Highlights
Gamete formation during sexual reproduction occurs by a specialized cell division program called meiosis, where two rounds of chromosome segregation follow one round of DNA replication; homologous chromosomes segregate in the first round and sister chromatids separate in the second
We show that Spata22shani/shani mutant spermatocytes have defective chromosome synapsis and fail to complete double-strand breaks (DSBs) repair during meiotic prophase, like Spata22-null mice (Hays et al 2017)
This study describes a novel point-mutated allele of the meiotic recombination gene Spata22 using a phenotype-based forwardgenetics screen
Summary
Gamete formation during sexual reproduction occurs by a specialized cell division program called meiosis, where two rounds of chromosome segregation follow one round of DNA replication; homologous chromosomes segregate in the first round and sister chromatids separate in the second. The meiotic cell division program contains an extended prophase, during which replicated homologous chromosomes pair and recombine. This creates temporary connections called crossovers that are essential to stabilize homologs on the metaphase spindle during segregation (Page and Hawley 2003; Hunter 2015). We lack clear understanding of how meiosis-specific proteins collaborate with ubiquitous repair proteins to specialize homologous recombination during meiosis. It is unclear whether the catalog of relevant vertebrate proteins important for meiotic recombination is complete
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