Institute of Physiological Chemistry, Technische Universität Dresden, Fiedlerstrasse 42, 01307 Dresden, Germany.
Nat Cell Biol. 2011 May;13(5):599-610. doi: 10.1038/ncb2213. Epub 2011 Apr 10.
Meiotic crossover formation between homologous chromosomes (homologues) entails DNA double-strand break (DSB) formation, homology search using DSB ends, and synaptonemal-complex formation coupled with DSB repair. Meiotic progression must be prevented until DSB repair and homologue alignment are completed, to avoid the formation of aneuploid gametes. Here we show that mouse HORMAD1 ensures that sufficient numbers of processed DSBs are available for successful homology search. HORMAD1 is needed for normal synaptonemal-complex formation and for the efficient recruitment of ATR checkpoint kinase activity to unsynapsed chromatin. The latter phenomenon was proposed to be important in meiotic prophase checkpoints in both sexes. Consistent with this hypothesis, HORMAD1 is essential for the elimination of synaptonemal-complex-defective oocytes. Synaptonemal-complex formation results in HORMAD1 depletion from chromosome axes. Thus, we propose that the synaptonemal complex and HORMAD1 are key components of a negative feedback loop that coordinates meiotic progression with homologue alignment: HORMAD1 promotes homologue alignment and synaptonemal-complex formation, and synaptonemal complexes downregulate HORMAD1 function, thereby permitting progression past meiotic prophase checkpoints.
同源染色体（同源物）之间的减数分裂交叉形成需要 DNA 双链断裂（DSB）的形成、使用 DSB 末端进行同源搜索，以及联会复合体的形成与 DSB 修复相结合。为了避免形成非整倍体配子，必须在 DSB 修复和同源物对齐完成之前防止减数分裂进程的进行。在这里，我们表明，小鼠 HORMAD1 确保有足够数量的已处理 DSB 可用于成功的同源搜索。HORMAD1 对于正常的联会复合体形成以及ATR 检查点激酶活性向未联会染色质的有效募集是必需的。后一种现象被认为在两性的减数分裂前期检查点中很重要。与该假设一致，HORMAD1 对于消除联会复合体缺陷的卵母细胞是必需的。联会复合体的形成导致染色体轴上 HORMAD1 的耗竭。因此，我们提出联会复合体和 HORMAD1 是协调同源物对齐与减数分裂进程的负反馈回路的关键组成部分：HORMAD1 促进同源物对齐和联会复合体的形成，而联会复合体下调 HORMAD1 功能，从而允许减数分裂前期检查点的进展。
