Adenovirus Core Protein VII Protects the Viral Genome from a DNA Damage Response at Early Times after Infection
Adenovirus Core Protein VII Protects the Viral Genome from a DNA Damage Response at Early Times after Infection
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DOI：
10.1128/jvi.02540-10
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发表时间：
2011-05-01
影响因子：
5.4
通讯作者：
Hearing, Patrick
中科院分区：
文献类型：
--
作者：
Karen, Kasey A.;Hearing, Patrick
腺病毒具有线性双链DNA基因组，细胞Mre 11-Rad 50-Nbs 1（MRN）DNA修复复合物将其视为双链断裂。如果不减弱，MRN激发双链断裂修复反应，阻断病毒DNA复制并将病毒基因组连接成多联体。有两组早期病毒蛋白抑制MRN复合物。E1 B-55 K/E4-ORF 6复合物募集E3泛素连接酶，并靶向MRN蛋白进行蛋白酶体依赖性降解。E4-ORF 3蛋白通过螯合作用抑制MRN。在这些早期蛋白表达之前阻止病毒基因组的MRN识别的机制以前是未知的。在这里，我们展示了腺病毒基因组中病毒核心蛋白VII的丢失与由于双链断裂修复反应而获得的检查点信号之间的时间相关性。虽然检查点信号传导对应于病毒基因组的识别，但核心蛋白VII与病毒基因组的结合和检查点信号传导在很大程度上是相互排斥的。已知转录从基因组释放蛋白VII，并且转录的抑制显示检查点信号传导的减少。最后，我们表明，Mre 11的核酸酶活性是在DNA损伤反应过程中抑制病毒DNA复制的关键。这些结果支持一个模型，涉及的核心蛋白VII的检查点信号的传入病毒基因组的保护，并表明，MRN依赖的DNA损伤反应的诱导可能会抑制腺病毒复制的物理掩蔽的DNA复制的起点，而不是改变它们的完整性。
Adenovirus has a linear, double-stranded DNA genome that is perceived by the cellular Mre11-Rad50-Nbs1 (MRN) DNA repair complex as a double-strand break. If unabated, MRN elicits a double-strand break repair response that blocks viral DNA replication and ligates the viral genomes into concatemers. There are two sets of early viral proteins that inhibit the MRN complex. The E1B-55K/E4-ORF6 complex recruits an E3 ubiquitin ligase and targets MRN proteins for proteasome-dependent degradation. The E4-ORF3 protein inhibits MRN through sequestration. The mechanism that prevents MRN recognition of the viral genome prior to the expression of these early proteins was previously unknown. Here we show a temporal correlation between the loss of viral core protein VII from the adenovirus genome and a gain of checkpoint signaling due to the double-strand break repair response. While checkpoint signaling corresponds to the recognition of the viral genome, core protein VII binding to and checkpoint signaling at viral genomes are largely mutually exclusive. Transcription is known to release protein VII from the genome, and the inhibition of transcription shows a decrease in checkpoint signaling. Finally, we show that the nuclease activity of Mre11 is dispensable for the inhibition of viral DNA replication during a DNA damage response. These results support a model involving the protection of the incoming viral genome from checkpoint signaling by core protein VII and suggest that the induction of an MRN-dependent DNA damage response may inhibit adenovirus replication by physically masking the origins of DNA replication rather than altering their integrity.