Phosphorylation of chromosome core components may serve as axis marks for the status of chromosomal events during mammalian meiosis.
Phosphorylation of chromosome core components may serve as axis marks for the status of chromosomal events during mammalian meiosis.
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DOI：
10.1371/journal.pgen.1002485
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发表时间：
2012-02
期刊：
影响因子：
4.5
通讯作者：
Höög C
中科院分区：
文献类型：
--
作者：
Fukuda T;Pratto F;Schimenti JC;Turner JM;Camerini-Otero RD;Höög C
减数分裂重组和同源染色体间的染色体联会是第一次减数分裂时染色体正确分离的必要条件。虽然重组和突触，以及检查点，监测这两个事件，发生在一个前期I特定的轴向染色体结构的背景下，它仍然不清楚如何染色体轴组件有助于这些过程。我们在这里表明，减数分裂染色体轴的许多蛋白质成分，包括SYCP 2，SYCP 3，HORMAD 1，HORMAD 2，SMC 3，STAG 3和REC 8，在前期I阶段被磷酸化后修饰。我们发现HORMAD 1和SMC 3在ATM/ATR检查点激酶的一个共有位点磷酸化，并且HORMAD 1和SMC 3的磷酸化形式优先定位于突触尚未发生的非突触染色体区域，但不定位于突触或去突触区域。我们研究了磷酸化事件的遗传要求，并揭示了HORMAD 1，HORMAD 2和SMC 3的磷酸化水平在减数分裂重组启动的情况下显著降低，而BRCA 1和SYCP 3是HORMAD 1和HORMAD 2磷酸化正常水平所需的，但不是SMC 3。有趣的是，HORMAD 1和HORMAD 2磷酸化的减少与MSUC（未突触染色质的减数分裂沉默）机制对未突触染色体的靶向受损有关，这表明这些翻译后事件有助于突触监视系统的调节。我们认为，染色体轴组件的修改作为信号，促进染色体事件，包括重组，检查点控制，转录和突触调节。减数分裂是产生单倍体精子和卵子的专门细胞分裂。为了使同源染色体在第一次减数分裂中准确分离，在前期Ⅰ阶段应在它们之间建立适当的染色体联会和重组。染色体联会和重组在减数分裂染色体轴的背景下进行。虽然使用基因敲除小鼠模型的研究已经揭示了染色体轴组分在哺乳动物减数分裂期间的多个染色体事件中发挥作用，但它们如何促进这些过程仍有待阐明。在这里，我们表明，许多哺乳动物减数分裂染色体轴蛋白磷酸化在空间和时间上不同的方式在前期I阶段。特别是，HORMAD 1和SMC 3的磷酸化被观察到优先在染色体区域的突触还没有发生。此外，在重组启动或染色体轴组织缺陷的突变睾丸细胞中，HORMAD 1和HORMAD 2的磷酸化减少。此外，突变的精母细胞不能正确地分配检查点蛋白，该检查点蛋白协调染色体突触与基因表达和减数分裂进程。因此，它是建议，染色体轴蛋白磷酸化作为整合轴标记的事件发生在减数分裂染色体上的状态。
Meiotic recombination and chromosome synapsis between homologous chromosomes are essential for proper chromosome segregation at the first meiotic division. While recombination and synapsis, as well as checkpoints that monitor these two events, take place in the context of a prophase I-specific axial chromosome structure, it remains unclear how chromosome axis components contribute to these processes. We show here that many protein components of the meiotic chromosome axis, including SYCP2, SYCP3, HORMAD1, HORMAD2, SMC3, STAG3, and REC8, become post-translationally modified by phosphorylation during the prophase I stage. We found that HORMAD1 and SMC3 are phosphorylated at a consensus site for the ATM/ATR checkpoint kinase and that the phosphorylated forms of HORMAD1 and SMC3 localize preferentially to unsynapsed chromosomal regions where synapsis has not yet occurred, but not to synapsed or desynapsed regions. We investigated the genetic requirements for the phosphorylation events and revealed that the phosphorylation levels of HORMAD1, HORMAD2, and SMC3 are dramatically reduced in the absence of initiation of meiotic recombination, whereas BRCA1 and SYCP3 are required for normal levels of phosphorylation of HORMAD1 and HORMAD2, but not of SMC3. Interestingly, reduced HORMAD1 and HORMAD2 phosphorylation is associated with impaired targeting of the MSUC (meiotic silencing of unsynapsed chromatin) machinery to unsynapsed chromosomes, suggesting that these post-translational events contribute to the regulation of the synapsis surveillance system. We propose that modifications of chromosome axis components serve as signals that facilitate chromosomal events including recombination, checkpoint control, transcription, and synapsis regulation. Meiosis is a specialized cell division to generate haploid sperm and eggs. For accurate segregation of homologous chromosomes during the first meiotic division, chromosome synapsis and recombination should be properly established between them during the prophase I stage. Chromosome synapsis and recombination proceed in the context of the meiotic chromosome axis. While studies using knockout mouse models have revealed that chromosome axis components play roles in multiple chromosomal events during mammalian meiosis, it remains to be elucidated how they contribute to the processes. Here, we show that many mammalian meiotic chromosome axis proteins are phosphorylated in a spatially and temporally distinct manner during the prophase I stage. Especially, phosphorylation of HORMAD1 and SMC3 was observed preferentially in chromosomal regions where synapsis has not occurred. Moreover, phosphorylation of HORMAD1 and HORMAD2 was reduced in mutant testicular cells that were defective in recombination initiation or chromosome axis organization. Additionally, the mutant spermatocytes failed to correctly distribute checkpoint proteins that coordinate chromosome synapsis with gene expression and meiotic progression. Thus, it is suggested that phosphorylation of chromosome axis proteins serves as integrative axis marks for the status of events that take place on meiotic chromosomes.
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影响因子：
11.4
作者：
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Pendas, Alberto M.
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作者：
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