ATM promotes the obligate XY crossover and both crossover control and chromosome axis integrity on autosomes.
ATM promotes the obligate XY crossover and both crossover control and chromosome axis integrity on autosomes.
复制标题
DOI：
10.1371/journal.pgen.1000076
复制
发表时间：
2008-05-23
期刊：
影响因子：
4.5
通讯作者：
Jasin M
中科院分区：
文献类型：
--
作者：
Barchi M;Roig I;Di Giacomo M;de Rooij DG;Keeney S;Jasin M
在大多数有性生殖生物的减数分裂过程中，重组形成同源母本和父本染色体之间的交叉，从而促进第一次减数分裂时染色体的正确分离。交换的数量和分布受到严格控制，但在大多数生物体（包括哺乳动物）中，对这种控制的因素知之甚少。在这里，我们提供的证据表明，ATM激酶或蛋白质是必不可少的适当的交换形成小鼠精母细胞。ATM缺陷导致人类和小鼠的多种表型，包括性腺萎缩。小鼠Atm−/−精母细胞在减数分裂I的中前期发生凋亡，但Atm−/−减数分裂表型被Spo 11杂合性部分挽救，因此Atm缺陷精母细胞进展到减数分裂中期I。引人注目的是，Spo 11 +/−Atm−/−精母细胞在性染色体上形成专性交换时有缺陷，尽管XY对通常被整合到性体中，并且像正常精母细胞一样在转录上失活。XY交叉缺陷与中期I的落后染色体的出现相关，这可能引发在这些细胞中观察到的广泛的中期凋亡。此外，在不存在ATM的情况下，常染色体上交叉的数量和分布的控制似乎是有缺陷的，因为标记最终交叉形成的位点的MLH 1焦点的总数增加，并且因为MLH 1焦点之间的干扰被扰乱。常染色体的轴表现出与正在进行的重组的位置相关的结构缺陷。总之，这些研究结果表明，ATM在交叉控制和染色体轴的完整性中发挥作用，并进一步表明，ATM是重要的协调减数分裂染色体动力学的这些功能。减数分裂是一种特殊的细胞分裂，产生生殖细胞，如精子和卵子。在大多数生物的减数分裂过程中，遗传信息通过同源重组的过程在同源的母本和父本染色体之间交换。这种重组形成同源染色体之间的连接，使它们能够在减数分裂细胞分裂时准确分离。胚胎发育缺陷会导致生殖细胞染色体数目异常，这是人类发育障碍和自然流产的主要原因。减数分裂重组受到严格控制，使得每对染色体经历至少一个交换重组事件，尽管每条染色体的平均交换数较低。此外，同一条染色体上的多个交叉往往是均匀和广泛分布的。这种控制的机制还没有很好地理解，但在这里，我们提供的证据表明，ATM蛋白是需要正常运行的这一过程（ES）在雄性小鼠。ATM长期以来一直被认为参与细胞对DNA损伤的反应。我们的研究揭示了这种蛋白质的新功能，也为减数分裂细胞确保遗传物质从一代准确传递到下一代的机制提供了新的见解。
During meiosis in most sexually reproducing organisms, recombination forms crossovers between homologous maternal and paternal chromosomes and thereby promotes proper chromosome segregation at the first meiotic division. The number and distribution of crossovers are tightly controlled, but the factors that contribute to this control are poorly understood in most organisms, including mammals. Here we provide evidence that the ATM kinase or protein is essential for proper crossover formation in mouse spermatocytes. ATM deficiency causes multiple phenotypes in humans and mice, including gonadal atrophy. Mouse Atm−/− spermatocytes undergo apoptosis at mid-prophase of meiosis I, but Atm−/− meiotic phenotypes are partially rescued by Spo11 heterozygosity, such that ATM-deficient spermatocytes progress to meiotic metaphase I. Strikingly, Spo11+/−Atm−/− spermatocytes are defective in forming the obligate crossover on the sex chromosomes, even though the XY pair is usually incorporated in a sex body and is transcriptionally inactivated as in normal spermatocytes. The XY crossover defect correlates with the appearance of lagging chromosomes at metaphase I, which may trigger the extensive metaphase apoptosis that is observed in these cells. In addition, control of the number and distribution of crossovers on autosomes appears to be defective in the absence of ATM because there is an increase in the total number of MLH1 foci, which mark the sites of eventual crossover formation, and because interference between MLH1 foci is perturbed. The axes of autosomes exhibit structural defects that correlate with the positions of ongoing recombination. Together, these findings indicate that ATM plays a role in both crossover control and chromosome axis integrity and further suggests that ATM is important for coordinating these features of meiotic chromosome dynamics. Meiosis is the specialized cell division that gives rise to reproductive cells such as sperm and eggs. During meiosis in most organisms, genetic information is exchanged between homologous maternal and paternal chromosomes through the process of homologous recombination. This recombination forms connections between homologous chromosomes that allow them to segregate accurately when the meiotic cell divides. Recombination defects can result in reproductive cells with abnormal chromosome numbers, which are a major cause of developmental disorders and spontaneous abortions in humans. Meiotic recombination is tightly controlled such that each pair of chromosomes undergoes at least one crossover recombination event despite a low average number of crossovers per chromosome. Moreover, multiple crossovers on the same chromosome tend to be evenly and widely spaced. Mechanisms of this control are not well understood, but here we provide evidence that ATM protein is required for normal operation of this process(es) in male mice. ATM has long been known to be involved in cellular responses to DNA damage. Our studies reveal a new function for this protein and also provide new insight into the mechanisms by which meiotic cells ensure accurate transmission of genetic material from one generation to the next.
登录
查看更多内容
影响因子：
3.3
作者：
Bartrand, AJ;Iyasu, D;Brush, GS
通讯作者：
Brush, GS
影响因子：
9.8
作者：
Froenicke, L;Anderson, LK;Ashley, T
通讯作者：
Ashley, T
影响因子：
9.8
作者：
Broman, KW;Weber, JL
通讯作者：
Weber, JL
影响因子：
64.5
作者：
Blat, Y;Protacio, RU;Kleckner, N
通讯作者：
Kleckner, N
影响因子：
2.7
作者：
Eaker, S;Cobb, J;Handel, MA
通讯作者：
Handel, MA