MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis.
MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis.
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DOI：
10.1371/journal.pgen.1000186
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发表时间：
2008-09-12
期刊：
影响因子：
4.5
通讯作者：
Cohen PE
中科院分区：
文献类型：
--
作者：
Holloway JK;Booth J;Edelmann W;McGowan CH;Cohen PE
已经描述了两条真核细胞处理双链断裂(DSB)作为交叉的途径，一条依赖于MutL同源物MLH1和MLH3，另一条依赖于结构特异的内切酶MUS81。哺乳动物MUS81与维持体细胞基因组稳定性有关，但对其在减数分裂中的作用知之甚少。MUS81缺失的小鼠最初被报道为有活力和可生育，减数分裂进程正常；然而，对MUS81缺失动物和WT对照的减数分裂进程进行更详细的检查发现，突变体中存在显著的减数分裂缺陷。这些包括较小的睾丸，成熟附睾精子的枯竭，粗线期小细胞以不受干扰的方式显著上调MLH1在染色体上的积累，以及无法修复的减数分裂DSB的子集。有趣的是，MUS81−/−动物精母细胞中的交叉数目是正常的，这表明控制两个不同的交叉途径的额外的整合机制。这项研究是对MUS81缺失小鼠减数分裂进程的第一次深入分析，我们的结果表明MUS81通路是哺乳动物交叉频率和位置的调节因素。在哺乳动物减数分裂过程中，没有进行有效的减数分裂染色体分离可能会导致后代出现非整倍体，这是导致人类妊娠丢失和出生缺陷的主要原因。减数分裂前期I的一个重要组成部分是母本和父本染色体之间的遗传信息交换，称为重组或交换，至少部分由错配修复蛋白MSH4-MSH5和MLH1-MLH3介导。在低等生物中，一个独特的交叉子集是由涉及MUS81内切酶的另一条途径产生的。之前对MUS81突变对小鼠的影响的研究表明，这些动物的生育能力没有不良影响。在这项研究中，我们报告了雄性和雌性MUS81小鼠减数分裂过程中微小但显著的缺陷，以及有趣的结果表明，MUS81蛋白对于哺乳动物的交叉控制是必不可少的。然而，MUS81似乎是MLH1-MLH3复合体正确定位到成对的同源染色体所必需的，而不是为了维持物理交叉，可见为交叉。这些结果表明，MUS81和MLH1-MLH3产生交叉的途径之间存在复杂的相互作用，因此，对于进一步了解交叉控制的复杂性以降低人类减数分裂错误率至关重要。
Two eukaryotic pathways for processing double-strand breaks (DSBs) as crossovers have been described, one dependent on the MutL homologs Mlh1 and Mlh3, and the other on the structure-specific endonuclease Mus81. Mammalian MUS81 has been implicated in maintenance of genomic stability in somatic cells; however, little is known about its role during meiosis. Mus81-deficient mice were originally reported as being viable and fertile, with normal meiotic progression; however, a more detailed examination of meiotic progression in Mus81-null animals and WT controls reveals significant meiotic defects in the mutants. These include smaller testis size, a depletion of mature epididymal sperm, significantly upregulated accumulation of MLH1 on chromosomes from pachytene meiocytes in an interference-independent fashion, and a subset of meiotic DSBs that fail to be repaired. Interestingly, chiasmata numbers in spermatocytes from Mus81−/− animals are normal, suggesting additional integrated mechanisms controlling the two distinct crossover pathways. This study is the first in-depth analysis of meiotic progression in Mus81-nullizygous mice, and our results implicate the MUS81 pathway as a regulator of crossover frequency and placement in mammals. Failure to undergo faithful meiotic chromosome segregation during mammalian meiosis can result in aneuploidy in the offspring and is a major cause of pregnancy loss and birth defects in humans. One essential component of meiotic prophase I is the exchange of genetic information between maternal and paternal chromosomes, known as recombination or crossing over, and is mediated, at least in part, by the mismatch repair proteins MSH4–MSH5 and MLH1–MLH3. A distinct subset of crossovers in lower organisms is generated by an alternate pathway involving Mus81 endonuclease. Previous studies into the impact of Mus81 mutations in mice revealed no adverse effect on the fertility of these animals. In this study, we report subtle, yet significant, defects in meiotic progression in male and female Mus81 mice, coupled with intriguing results showing that MUS81 protein is essential for crossover control in mammals. MUS81 appears to be required for correct localization of MLH1–MLH3 complexes to paired homologous chromosomes, however, not for the maintenance of physical crossovers, visualized as chiasmata. These results show a complex interplay between the MUS81 and MLH1–MLH3 pathways for generation of crossovers and, as such, are critical to the further understanding of the intricacies of crossover control with a view to reducing meiotic error rate in humans.
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