Analyses of the function of Mcmdc2 in DNA repair during meiosis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06159
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: National Institute of Genetics
• Principal Investigator: Sakai Noriyoshi 国立遺伝学研究所, 遺伝形質研究系, 准教授 (50202081)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 減数分裂 / Mcmdc2 / ゼブラフィッシュ

Outline of Final Research Achievements

Generation and repair of DNA double strand breaks (DSB) during homologous recombination (HR) is a key step in meiosis that promotes proper alignment and segregation of homologous chromosomes; however, the mechanisms underlying this process remain largely unknown. In this study, we identified the causative gene in the zebrafish ENU mutant imo, which exhibits abnormal meiosis, by complementation testing with mcmdc2 knockout. We then analyzed the dynamics of the synaptonemal complex Sycp1 and Sycp3, the DNA recombinase Dmc1, the DSB marker phosphorylated histone H2AX, the DNA repair protein Msh5, and telomere pairing in the mutants. Our results suggest that the formation and stabilization of DSB repair intermediates during HR are not normal in this mutant. We also found that although chromosomal aneuploidy occurred in oocytes, oogenesis progressed.

Free Research Field

発生生物学

Academic Significance and Societal Importance of the Research Achievements

Mcmdc2は、ショウジョウバエとマウスにおいてDSB修復に機能する新規因子であることが示唆されているが、その分子機構は未知である。本研究から、ゼブラフィッシュではMcmdc2はDSB修復中間体の形成・安定化に働き、精子形成過程は減数分裂期で停止する一方で、卵母細胞が減数分裂を超えて発達することが示された。この因子が染色体の正常な分配に一義的に働くことが予想される。本研究では、3xFLAG-Stag-mcmdc2系統やMcmdc2の協働制御因子Mcm8の変異体を作出できているため、今後、これらを用いて解析を進めることで、この複合体が染色体分配に果たす役割を解明できると期待される。