The genetic landscape of male infertility is highly complex. It is estimated that at least 1000–2000 genes are involved in human and mouse infertility. Although functional analyses have been performed on hundreds of genes, many others still have unknown functions. Generating gene-editing mice is a powerful tool for exploring whether a given gene is essential for male reproduction in vivo. In the current study, we investigated the function of six genes, Efcab7, Tekt3, Mlf1, Rp1l1, Agbl2, and Tmsb15a, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system. Individual disruption of these six genes did not cause overt male sterility in mice under standard breeding conditions. Phenotypic analyses at 8–10 weeks of age generally showed that most reproductive parameters were comparable to those of wild-type controls; however, we observed significant sperm motility alterations in Tekt3-mutant mice (decreased motility) and Rp1l1-mutant mice (increased motility), as well as flagellar abnormalities in Tekt3 mutants. In summary, these findings suggest that complete or near-complete disruption of the tested murine alleles does not cause overt male infertility, providing useful functional evidence for interpretation of candidate variants while not excluding human-specific or allele-specific effects.
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Open Access
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Open Access
Original Article
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The newly defined cancer-testis (CT) gene, MEIOB, was previously found to play key roles in DNA double-strand break (DSB) repair. In this study, we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers (TNBCs).
The Cancer Genome Atlas database was used to quantify the expression of MEIOB. Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC. The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro. Patient-derived xenograft (PDX) models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.
We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors, especially TNBCs. Its activation was significantly associated with poor survival in breast cancer patients [overall, hazard ratio (HR) = 1.90 (1.16–2.06); TNBCs: HR = 7.05 (1.16–41.80)]. In addition, we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells. Further analysis showed that MEIOB participated in DSB repair in TNBCs. However, in contrast to its function in meiosis, it mediated homologous recombination deficiency (HRD) through the activation of polyADP-ribose polymerase (PARP)1 by interacting with YBX1. Furthermore, activated MEIOB was shown to confer sensitivity to PARP inhibitors, which was confirmed in PDX models.
MEIOB played an oncogenic role in TNBC through its involvement in HRD. In addition, dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors, so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.
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