The SMC-5/6 Complex and the HIM-6 (BLM) Helicase Synergistically Promote Meiotic Recombination Intermediate Processing and Chromosome Maturation during Caenorhabditis elegans Meiosis.
The SMC-5/6 Complex and the HIM-6 (BLM) Helicase Synergistically Promote Meiotic Recombination Intermediate Processing and Chromosome Maturation during Caenorhabditis elegans Meiosis.
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DOI：
10.1371/journal.pgen.1005872
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发表时间：
2016-03
期刊：
影响因子：
4.5
通讯作者：
Gartner A
中科院分区：
文献类型：
--
作者：
Hong Y;Sonneville R;Agostinho A;Meier B;Wang B;Blow JJ;Gartner A
减数分裂重组对于修复程序性双链断裂（DSB）以在减数分裂期间产生交叉（CO）至关重要。减数分裂重组中间体的高效加工不仅需要各种解离酶，还需要适当的减数分裂染色体结构。 Smc5/6复合体属于染色体结构维持（SMC）家族，与粘连蛋白和凝缩蛋白密切相关。尽管 Smc5/6 复合体参与减数分裂过程中重组中间体的加工，但尚不清楚 Smc5/6 如何控制减数分裂 DSB 修复。在这里，我们利用秀丽隐杆线虫证明了 SMC-5/6 复合物与 HIM-6（减数分裂重组过程中人类布卢姆综合征解旋酶 (BLM) 的直系同源物）具有协同作用。 SMC-5/6 复合物和 HIM-6 的协同作用对于加工重组中间体、CO 调节和二价成熟非常重要。仔细检查减数分裂染色体形态揭示了 smc-5 中染色体间桥的积累； Him-6 双突变体，导致减数分裂细胞分裂过程中染色体分离受损。有趣的是，我们发现smc-5的杀伤力； Him-6 可以通过丢失保守的 BRCA1 直向同源物 BRC-1 来挽救。此外，smc-5和him-6的联合缺失导致凝缩蛋白分布不规则，并导致染色体解凝缩缺陷，让人想起凝缩蛋白耗尽。 BRC-1 耗尽也可以挽救凝缩蛋白耗尽所带来的致死性。我们的结果表明，SMC-5/6 和 HIM-6 可以通过控制减数分裂过程中的染色体结构来协同调节重组中间代谢并抑制异位重组。减数分裂是形成单倍体配子所需的特殊细胞分裂形式。在减数分裂过程中，DNA双链断裂被酶促诱导，然后通过减数分裂重组途径修复。减数分裂重组对于遗传多样性和减数分裂过程中染色体的准确分离至关重要。减数分裂重组修复可以使用同系物或姐妹染色单体作为模板来生成不同的重组中间体。重组中间体必须通过特定的核酸内切酶和 BLM 解旋酶来解析或溶解。未解决的重组中间体会导致染色质桥的形成并扰乱正常的染色体分离。在这项研究中，我们表明，BLM 解旋酶 HIM-6 和进化上保守的 SMC-5/6 复合体的协同作用对于线虫减数分裂重组中间体的有序处理、正确的交叉 (CO) 形成和随后的染色体分离非常重要。值得注意的是，HIM-6 是减数分裂 CO 正常分布所必需的。我们还提出，SMC-5/6 和 HIM-6 之间的相互作用在高度浓缩和有序的染色体结构的形成中起着至关重要的作用，该结构限制了 BRC-1 依赖性异位重组。
Meiotic recombination is essential for the repair of programmed double strand breaks (DSBs) to generate crossovers (COs) during meiosis. The efficient processing of meiotic recombination intermediates not only needs various resolvases but also requires proper meiotic chromosome structure. The Smc5/6 complex belongs to the structural maintenance of chromosome (SMC) family and is closely related to cohesin and condensin. Although the Smc5/6 complex has been implicated in the processing of recombination intermediates during meiosis, it is not known how Smc5/6 controls meiotic DSB repair. Here, using Caenorhabditis elegans we show that the SMC-5/6 complex acts synergistically with HIM-6, an ortholog of the human Bloom syndrome helicase (BLM) during meiotic recombination. The concerted action of the SMC-5/6 complex and HIM-6 is important for processing recombination intermediates, CO regulation and bivalent maturation. Careful examination of meiotic chromosomal morphology reveals an accumulation of inter-chromosomal bridges in smc-5; him-6 double mutants, leading to compromised chromosome segregation during meiotic cell divisions. Interestingly, we found that the lethality of smc-5; him-6 can be rescued by loss of the conserved BRCA1 ortholog BRC-1. Furthermore, the combined deletion of smc-5 and him-6 leads to an irregular distribution of condensin and to chromosome decondensation defects reminiscent of condensin depletion. Lethality conferred by condensin depletion can also be rescued by BRC-1 depletion. Our results suggest that SMC-5/6 and HIM-6 can synergistically regulate recombination intermediate metabolism and suppress ectopic recombination by controlling chromosome architecture during meiosis. Meiosis is a special form of cell division needed for the formation of haploid gametes. During meiosis, DNA double-strand breaks are enzymatically induced and then repaired by the meiotic recombination pathway. Meiotic recombination is essential for genetic diversity and for accurate segregation of chromosomes during meiosis. Meiotic recombinational repair can either use the homolog or the sister chromatid as a template to generate different recombination intermediates. Recombination intermediates must be resolved or dissolved by specific endonucleases and the BLM helicase. Unresolved recombination intermediates lead to formation of chromatin bridges and perturb proper chromosome segregation. In this study we show that the concerted action of the BLM helicase HIM-6 and the evolutionarily conserved SMC-5/6 complex are important for the ordered processing of meiotic recombination intermediates, proper crossover (CO) formation and subsequent chromosome segregation in C. elegans. Notably, HIM-6 is required for the normal distribution of meiotic COs. We also propose that the interplay between SMC-5/6 and HIM-6 has a crucial role in the formation of a highly condensed and ordered chromosomal structure, which constrains BRC-1 dependent ectopic recombination.