1, We have identified novel recombination regulators MEILB2 and BRME1 in mice. We found that BRME1-MEILB2 forms complex with the cancer suppressor BRCA2 and functions as a localizer of BRCA2 to meiotic DNA-break sites. Further by making knockout mice, we have established the essential role of the BRME1-MEILB2-BRCA2 ternary complex in the regulation of meiotic recombination. These works were published in Nature Communications (2020) and Nature Structural Molecular Biology (2021).
2, We have found that the MYB-like DNA-binding (MYB) domain of meiotic telomere protein TERB1 has a role in the suppression of telomere erosion during meiotic telomere movements. Without the TERB1 MYB domain, meiotic telomeres are fused, bridged, or ultimately eroded during meiotic prophase I. Our findings suggest that the TERB1 MYB domain might be required for the maintenance of telomeric DNA and, thus, genomic integrity in the long evolutionary period. This work is published in Cell Reports (2022)
3, We have identified that spindle formation in male meiosis I requires the cytoplasmic dynein complex containing a testis-upregulated light chain paralog, DYNLRB2. We showed that DYNLRB2 ensures spindle bipolarity in meiosis I through two distinct pathways: 1) maintaining centriole engagement in metaphase I and 2) recruiting NuMA to the spindle pole. This work is published in Nature Communications (2023)
4, We have discovered that the nuclear envelope in male meiosis I undergoes modification through the synthesis and incorporation of very-long-chain polyunsaturated fatty acids (VLC-PUFAs) by the AdipoR2 and ELOVL2 functional axis. This ensures a highly fluid membrane environment necessary for the peripheral distribution of meiotic telomeres and thus for faithful homolog synapsis/recombination and ultimately male fertility.
Overall, there were several unexpected discoveries that surpassed the initial research proposal. For instance, the control of spindle formation by DYNLRB2 was not originally included in the research plan. DYNLRB2 was identified by the KASH5 immunoprecipitation in this project and we reveiled their unexpect roles after making and analyzing the knockout mice. Additionally, the regulation of nuclear membrane fluidity by AdipoR2-ELOVL2 originated from an unexpected idea born out of collaboration with Marc Pilon's lab at the University of Gothenburg. Therefore, we conclude that the research progressed very productively and efficiently as a whole. Furthermore, the outcomes of this study are poised to provide foundational knowledge useful for understanding the causes of human infertility in the future and consequently for treatment. Indeed, concerning proteins like TERB1 and MEILB2 that we analyzed in this project, mutations have been consistently reported by several clinical research groups in infertility patients recently.
