Relocalization of the Mre11-Rad50-Nbs1 complex by the adenovirus E4 ORF3 protein is required for viral replication
Relocalization of the Mre11-Rad50-Nbs1 complex by the adenovirus E4 ORF3 protein is required for viral replication
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DOI：
10.1128/jvi.79.10.6207-6215.2005
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发表时间：
2005-05-01
影响因子：
5.4
通讯作者：
Hearing, P
中科院分区：
文献类型：
--
作者：
Evans, JD;Hearing, P
腺病毒复制受核蛋白复合物的重新定位或修饰控制，包括早幼粒细胞白血病蛋白（PML）核结构域和Mre 11-Rad 50-Nbs 1（MRN）DNA损伤机制。在这项研究中，我们证明了E4 ORF 3蛋白影响PML和MRN蛋白在感染后早期重新定位到细胞核内的相似结构。这些蛋白与E4 ORF 3共定位。通过对特定病毒突变体的分析，我们发现感染后早期NIRN重组与病毒DNA复制结构域的建立之间存在直接相关性。此外，MRN组件的重组可能与E4 ORF 3重排PML的能力无关。在感染的后期，MRN复合物的组分分散在细胞核内，Nbs 1在病毒复制中心内发现，Rad 50仍然与E4 ORF 3一起定位，Mre 11被降解。在缺乏Mre 11或Nbs 1活性的细胞中，E4突变病毒的互补作用强调了病毒调节MRN复合物的重要性。这些结果说明了核组织在病毒生长中的重要性，并表明E4 ORF 3调节PML核体和MRN复合体的活性以刺激病毒复制程序。
Adenovirus replication is controlled by the relocalization or modification of nuclear protein complexes, including promyelocytic leukemia protein (PML) nuclear domains and the Mre11-Rad50-Nbs1 (MRN) DNA damage machinery. In this study, we demonstrated that the E4 ORF3 protein effects the relocalization of both PML and MRN proteins to similar structures within the nucleus at early times after infection. These proteins colocalize with E4 ORF3. Through the analysis of specific viral mutants, we found a direct correlation between NIRN reorganization at early times after infection and the establishment of viral DNA replication domains. Further, the reorganization of MRN components may be uncoupled from the ability of E4 ORF3 to rearrange PML. At later stages of infection, components of the MRN complex disperse within the nucleus, Nbs1 is found within viral replication centers, Rad50 remains localized with E4 ORF3, and Mre11 is degraded. The importance of viral regulation of the MRN complex is underscored by the complementation of E4 mutant viruses in cells that lack Mre11 or Nbs1 activity. These results illustrate the importance of nuclear organization in virus growth and suggest that E4 ORF3 regulates activities in both PML nuclear bodies and the MRN complex to stimulate the viral replication program.