The Mre11/Rad50/Nbs1 complex limits adeno-associated virus transduction and replication
The Mre11/Rad50/Nbs1 complex limits adeno-associated virus transduction and replication
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DOI：
10.1128/jvi.01523-07
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发表时间：
2007-12-01
影响因子：
5.4
通讯作者：
Weitzman, Matthew D.
中科院分区：
文献类型：
--
作者：
Schwartz, Rachel A.;Palacios, Jose Alejandro;Weitzman, Matthew D.
腺相关病毒 (AAV) 是一种细小病毒，具有小的单链 DNA 基因组，依赖于细胞复制机制以及共感染辅助病毒提供的功能。宿主因素对 AAV 感染的影响尚不清楚。我们探索了腺病毒提供的 AAV 辅助功能与细胞 DNA 修复蛋白之间的联系。腺病毒 E1b55K/E4orf6 蛋白诱导细胞 Mre11 修复复合物 (MRN) 降解，以促进高效腺病毒感染。这些病毒蛋白还增强重组 AAV 转导，并为野生型 AAV 复制提供重要的辅助功能。在这里，我们表明 MRN 对 AAV 构成障碍，并且 E1b55K/E4orf6 提供的辅助功能涉及 MRN 降解。使用荧光方法可视化病毒基因组，我们在病毒 DNA 水平上显示了效果。 MRN 成分在 AAV 复制中心积累并识别病毒反向末端重复序列。总之，我们的数据表明 AAV 是 MRN 的目标，并且已经进化到利用降解这些细胞因子的腺病毒蛋白。
Adeno-associated virus (AAV) is a parvovirus with a small single-stranded DNA genome that relies on cellular replication machinery together with functions supplied by coinfecting helper viruses. The impact of host factors on AAV infection is not well understood. We explored the connection between AAV helper functions supplied by adenovirus and cellular DNA repair proteins. The adenoviral E1b55K/E4orf6 proteins induce degradation of the cellular Mre11 repair complex (MRN) to promote productive adenovirus infection. These viral proteins also augment recombinant AAV transduction and provide crucial helper functions for wild-type AAV replication. Here, we show that MRN poses a barrier to AAV and that the helper function provided by E1b55K/E4orf6 involves MRN degradation. Using a fluorescent method to visualize the viral genome, we show an effect at the viral DNA level. MRN components accumulate at AAV replication centers and recognize the viral inverted terminal repeats. Together, our data suggest that AAV is targeted by MRN and has evolved to exploit adenoviral proteins that degrade these cellular factors.