Department of Biomedical Sciences, Cornell University, Ithaca, New York 14850, USA.
Genetics. 2011 Sep;189(1):71-82. doi: 10.1534/genetics.111.130674. Epub 2011 Jul 12.
Chiasmata resulting from interhomolog recombination are critical for proper chromosome segregation at meiotic metaphase I, thus preventing aneuploidy and consequent deleterious effects. Recombination in meiosis is driven by programmed induction of double strand breaks (DSBs), and the repair of these breaks occurs primarily by recombination between homologous chromosomes, not sister chromatids. Almost nothing is known about the basis for recombination partner choice in mammals. We addressed this problem using a genetic approach. Since meiotic recombination is coupled with synaptonemal complex (SC) morphogenesis, we explored the role of axial elements--precursors to the lateral element in the mature SC--in recombination partner choice, DSB repair pathways, and checkpoint control. Female mice lacking the SC axial element protein SYCP3 produce viable, but often aneuploid, oocytes. We describe genetic studies indicating that while DSB-containing Sycp3-/- oocytes can be eliminated efficiently, those that survive have completed repair before the execution of an intact DNA damage checkpoint. We find that the requirement for DMC1 and TRIP13, proteins normally essential for recombination repair of meiotic DSBs, is substantially bypassed in Sycp3 and Sycp2 mutants. This bypass requires RAD54, a functionally conserved protein that promotes intersister recombination in yeast meiosis and mammalian mitotic cells. Immunocytological and genetic studies indicated that the bypass in Sycp3-/- Dmc1-/- oocytes was linked to increased DSB repair. These experiments lead us to hypothesize that axial elements mediate the activities of recombination proteins to favor interhomolog, rather than intersister recombinational repair of genetically programmed DSBs in mice. The elimination of this activity in SYCP3- or SYCP2-deficient oocytes may underlie the aneuploidy in derivative mouse embryos and spontaneous abortions in women.
交叉在减数分裂中期 I 中同源重组对于正确的染色体分离至关重要，从而防止非整倍体和随后的有害影响。减数分裂中的重组由程序性诱导双链断裂（DSB）驱动，这些断裂的修复主要通过同源染色体之间的重组发生，而不是姐妹染色单体之间的重组。几乎不知道哺乳动物重组伙伴选择的基础。我们使用遗传方法解决了这个问题。由于减数分裂重组与联会复合体（SC）形态发生偶联，我们探索了轴元件——成熟 SC 中侧元件的前体——在重组伙伴选择、DSB 修复途径和检查点控制中的作用。缺乏 SC 轴元件蛋白 SYCP3 的雌性小鼠产生有活力但经常是非整倍体的卵子。我们描述了遗传研究表明，虽然含有 DSB 的 Sycp3-/-卵子可以有效地消除，但那些存活下来的卵子在完整的 DNA 损伤检查点执行之前已经完成了修复。我们发现，对于 DMC1 和 TRIP13 蛋白的需求，通常对减数分裂 DSB 的重组修复至关重要，在 Sycp3 和 Sycp2 突变体中大大绕过。这种旁路需要 RAD54，一种在酵母减数分裂和哺乳动物有丝分裂细胞中促进姐妹染色单体间重组的功能保守蛋白。免疫细胞化学和遗传研究表明，Sycp3-/-Dmc1-/-卵子中的旁路与 DSB 修复增加有关。这些实验使我们假设轴元件介导重组蛋白的活性，以有利于同源重组，而不是小鼠中遗传编程的 DSB 的姐妹染色单体间重组修复。在 SYCP3 或 SYCP2 缺陷型卵子中消除这种活性可能是衍生小鼠胚胎非整倍体和女性自发性流产的基础。
