A role for MRE11, NBS1, and recombination junctions in replication and stable maintenance of EBV episomes.
A role for MRE11, NBS1, and recombination junctions in replication and stable maintenance of EBV episomes.
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MRE11，NBS1和重组连接的角色在复制和稳定的EBV插发体维护中。
DOI：
10.1371/journal.pone.0001257
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发表时间：
2007-12-05
期刊：
影响因子：
3.7
通讯作者：
Lieberman, Paul M.
中科院分区：
文献类型：
--
作者：
Dheekollu, Jayaraju;Deng, Zhong;Wiedmer, Andreas;Weitzman, Matthew D.;Lieberman, Paul M.
在DNA复制起点处形成的双链样结构可能有助于复制保真度、姐妹染色单体凝聚、染色体分离和整体基因组稳定性。EB病毒（EBV）质粒复制起点（OriP）通过知之甚少的机制提供附加型基因组稳定性。我们发现重组修复蛋白MRE11和NBS1以TRF2和细胞周期依赖的方式被募集到OriP的二联体对称（DS）区域。通过siRNA消耗MRE 11或NBS1抑制OriP复制并使病毒附加体不稳定。OriP质粒的维持在MRE 11和NBS1亚型成纤维细胞系中是有缺陷的，并且在来自NBS1突变个体的类成纤维细胞系中仅检测到整合的非附加型EBV。OriP DNA的二维琼脂糖凝胶分析显示，在S期中OriP处形成类似Holliday连接的重组样结构。MRE 11和NBS1与DS的关联与复制叉暂停和起点激活一致，这先于重组结构的形成。我们认为NBS 1和MRE 11促进了对于EB病毒附加体维持和基因组稳定性至关重要的复制相关重组连接。
Recombination-like structures formed at origins of DNA replication may contribute to replication fidelity, sister chromatid cohesion, chromosome segregation, and overall genome stability. The Epstein-Barr Virus (EBV) origin of plasmid replication (OriP) provides episomal genome stability through a poorly understood mechanism. We show here that recombinational repair proteins MRE11 and NBS1 are recruited to the Dyad Symmetry (DS) region of OriP in a TRF2- and cell cycle-dependent manner. Depletion of MRE11 or NBS1 by siRNA inhibits OriP replication and destabilized viral episomes. OriP plasmid maintenance was defective in MRE11 and NBS1 hypomorphic fibroblast cell lines and only integrated, non-episomal forms of EBV were detected in a lympoblastoid cell line derived from an NBS1-mutated individual. Two-dimensional agarose gel analysis of OriP DNA revealed that recombination-like structures resembling Holliday-junctions form at OriP in mid S phase. MRE11 and NBS1 association with DS coincided with replication fork pausing and origin activation, which preceded the formation of recombination structures. We propose that NBS1 and MRE11 promote replication-associated recombination junctions essential for EBV episomal maintenance and genome stability.
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