Genetic Evidence That Synaptonemal Complex Axial Elements Govern Recombination Pathway Choice in Mice
Genetic Evidence That Synaptonemal Complex Axial Elements Govern Recombination Pathway Choice in Mice
复制标题
DOI：
10.1534/genetics.111.130674
复制
发表时间：
2011-09-01
期刊：
影响因子：
3.3
通讯作者：
Schimenti, John C.
中科院分区：
文献类型：
--
作者：
Li, Xin Chenglin;Bolcun-Filas, Ewelina;Schimenti, John C.
同源重组产生的交叉对于减数分裂中期I染色体的正确分离至关重要，从而防止非整倍性和随后的有害影响。减数分裂中的减数分裂是由双链断裂（DSB）的程序性诱导驱动的，这些断裂的修复主要通过同源染色体之间的重组而不是姐妹染色单体之间的重组发生。几乎没有人知道哺乳动物重组伴侣选择的基础。我们用遗传学的方法解决了这个问题。由于减数分裂重组与联会复合体（SC）的形态发生相结合，我们探讨了轴向元素的作用-前体的成熟SC中的横向元素-在重组伴侣的选择，DSB修复途径，和检查点控制。缺乏SC轴元件蛋白SYCP 3的雌性小鼠产生有活力的卵母细胞，但通常是非整倍体的卵母细胞。我们描述的遗传研究表明，虽然含有DSB的Sycp 3（-/-）卵母细胞可以有效地消除，那些幸存下来的完成修复之前，执行一个完整的DNA损伤检查点。我们发现，DMC 1和TRIP 13，蛋白质通常是必不可少的减数分裂DSB的重组修复的要求，基本上绕过Sycp 3和Sycp 2突变体。这种旁路需要RAD 54，一种功能保守的蛋白质，促进酵母减数分裂和哺乳动物有丝分裂细胞中的姐妹间重组。免疫细胞学和遗传学研究表明，Sycp 3（-/-）Dmc 1（-/-）卵母细胞中的旁路与DSB修复增加有关。这些实验使我们假设，轴元件介导的重组蛋白的活动，有利于同源物，而不是intersister重组修复的遗传编程DSB在小鼠中。SYCP 3或SYCP 2缺陷卵母细胞中这种活性的消除可能是衍生小鼠胚胎非整倍体和妇女自然流产的基础。
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.