Mouse pachytene checkpoint 2 (trip13) is required for completing meiotic recombination but not synapsis.
Mouse pachytene checkpoint 2 (trip13) is required for completing meiotic recombination but not synapsis.
复制标题
完成减数分裂重组而不是突触需要小鼠Pachytene检查点2（TRIP13）。
DOI：
10.1371/journal.pgen.0030130
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发表时间：
2007-08
期刊：
影响因子：
4.5
通讯作者：
Schimenti JC
中科院分区：
文献类型：
--
作者：
Li XC;Schimenti JC
在哺乳动物减数分裂中，同源染色体突触伴随着重组。与大多数真核生物一样，哺乳动物减数细胞也有检查点来监测这些过程的保真度。我们报道了粗线素检查点2 （PCH2）的小鼠同源物（Trip13）， PCH2是酿酒酵母和秀丽隐杆线虫突触检查点的重要组成部分，是两性完成减数分裂所必需的。trip13缺陷小鼠在出生前后表现出厚皮瘤时精母细胞死亡和卵母细胞丢失。突变精子细胞的染色体完全突触，但保留了几个重组中间体标记，包括RAD51， BLM和RPA。这些染色体也表现出交叉标记MLH1和MLH3，并且突变精子细胞的冈田酸处理导致双价染色体进展到中期I。双突变分析表明，重组和突触基因Spo11、Mei1、Rec8和Dmc1均上位于Trip13，提示Trip13在小鼠中不具有减数分裂检查点功能。我们的数据表明，在链入侵后完成重组事件的一个子集需要TRIP13，但可能不是那些注定要交叉的重组事件。据我们所知，这是第一个在哺乳动物减数分裂中分离重组缺陷和asynapsis的模型，并提供了第一个证据，证明未修复的DNA损伤单独可以触发小鼠的pachytene检查点反应。至关重要的是，精子和卵子携带的染色体包含产生它们的个体基因组的忠实代表。在减数分裂过程中，每条染色体的母本和父本拷贝彼此“突触”（变得紧密相连），通过重组过程交换遗传物质，然后在两次减数分裂细胞分裂的第一次分裂成子细胞。复杂的染色体行为容易出错，因此大多数生物体都进化出了减数分裂“检查点”，以监测染色体突触的保真度和DNA损伤的修复。这些检查点导致有缺陷的细胞自我毁灭，而不是产生有缺陷的精子或卵子。我们研究了删除小鼠Trip13的影响，该基因在遥远的生物体中起着减数分裂检查点控制的关键作用。这些实验表明，在修复断裂的DNA分子所需的减数分裂的两类重组中，Trip13是必需的，而不是具有检查点的作用。染色体仍然正常结合，但由于卵母细胞和精母细胞大量死亡，动物不育。这些结果表明，除了对突触失败做出反应的检查点外，还存在一个专门检测由于重组失败而导致的未修复的DNA损伤的检查点。
In mammalian meiosis, homologous chromosome synapsis is coupled with recombination. As in most eukaryotes, mammalian meiocytes have checkpoints that monitor the fidelity of these processes. We report that the mouse ortholog (Trip13) of pachytene checkpoint 2 (PCH2), an essential component of the synapsis checkpoint in Saccharomyces cerevisiae and Caenorhabditis elegans, is required for completion of meiosis in both sexes. TRIP13-deficient mice exhibit spermatocyte death in pachynema and loss of oocytes around birth. The chromosomes of mutant spermatocytes synapse fully, yet retain several markers of recombination intermediates, including RAD51, BLM, and RPA. These chromosomes also exhibited the chiasmata markers MLH1 and MLH3, and okadaic acid treatment of mutant spermatocytes caused progression to metaphase I with bivalent chromosomes. Double mutant analysis demonstrated that the recombination and synapsis genes Spo11, Mei1, Rec8, and Dmc1 are all epistatic to Trip13, suggesting that TRIP13 does not have meiotic checkpoint function in mice. Our data indicate that TRIP13 is required after strand invasion for completing a subset of recombination events, but possibly not those destined to be crossovers. To our knowledge, this is the first model to separate recombination defects from asynapsis in mammalian meiosis, and provides the first evidence that unrepaired DNA damage alone can trigger the pachytene checkpoint response in mice. It is critical that the chromosomes carried by sperm and eggs contain faithful representations of the genome of the individual that produced them. During the process of meiosis, the maternal and paternal copies of each chromosome “synapse” with each other (become tightly associated), exchange genetic material via the process of recombination, then separate into daughter cells in the first of two meiotic cell divisions. The intricate chromosome behavior is subject to errors, so most organisms have evolved meiotic “checkpoints” that monitor fidelity of chromosome synapsis and repair of DNA damage. These checkpoints cause defective cells to self destruct rather than generate defective sperm or eggs. We studied the effects of deleting mouse Trip13, a gene that in distant organisms plays a key role in meiotic checkpoint control. These experiments revealed that instead of having a checkpoint role, Trip13 is required for one of the two major classes of recombination in meiosis that is required for repairing broken DNA molecules. The chromosomes still synapsed normally, but animals were sterile due to massive death of oocytes and spermatocytes. These results indicate that, in addition to a checkpoint that responds to failed synapsis, one exists to specifically detect unrepaired DNA damage that is due to failed recombination.