Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
mBio. 2019 Mar 19;10(2):e00152-19. doi: 10.1128/mBio.00152-19.
Human papillomaviruses (HPVs) are important pathogens with a significant medical burden. HPV genomes replicate in infected cells via bidirectional theta replication and a poorly understood unidirectional mechanism. In this report, we provide evidence that the previously described interaction between the viral E1 helicase and the cellular UAF1-USP1 deubiquitinating enzyme complex, a member of the Fanconi anemia DNA damage response pathway, is required for the completion of the bidirectional theta replication of the HPV11 genome and the subsequent initiation of the unidirectional replication. We show that unidirectional replication proceeds via theta structures and is supported by the cellular Bloom helicase, which interacts directly with E1 and whose engagement in HPV11 replication requires UAF1-USP1 activity. We propose that the unidirectional replication of the HPV11 genome initiates from replication fork restart events. These findings suggest a new role for the Fanconi anemia pathway in HPV replication. Human papillomaviruses (HPVs) are important pathogens that replicate their double-stranded circular DNA genome in the nucleus of infected cells. HPV genomes replicate in infected cells via bidirectional theta replication and a poorly understood unidirectional mechanism, and the onset of viral replication requires the engagement of cellular DNA damage response pathways. In this study, we showed that the previously described interaction between the viral E1 helicase and the cellular UAF1-USP1 complex is necessary for the completion of bidirectional replication and the subsequent initiation of the unidirectional replication mechanism. Our results suggest HPVs may use the cellular Fanconi anemia DNA damage pathway to achieve the separation of daughter molecules generated by bidirectional theta replication. Additionally, our results indicate that the unidirectional replication of the HPV genome is initiated from restarted bidirectional theta replication forks.
人乳头瘤病毒（HPV）是一种重要的病原体，具有重大的医学负担。HPV 基因组通过双向θ复制和一种尚未完全了解的单向机制在感染细胞中复制。在本报告中，我们提供了证据表明，病毒 E1 解旋酶与细胞 UAF1-USP1 去泛素化酶复合物之间先前描述的相互作用，是 HPV11 基因组双向θ复制完成以及随后单向复制起始所必需的。我们表明，单向复制通过θ结构进行，并得到细胞 Bloom 解旋酶的支持，该酶直接与 E1 相互作用，其在 HPV11 复制中的参与需要 UAF1-USP1 活性。我们提出 HPV11 基因组的单向复制从复制叉重启动事件开始。这些发现为 HPV 复制中范可尼贫血途径的新作用提供了依据。人乳头瘤病毒（HPV）是一种重要的病原体，其双链环状 DNA 基因组在感染细胞的核内复制。HPV 基因组通过双向θ复制和一种尚未完全了解的单向机制在感染细胞中复制，病毒复制的开始需要细胞 DNA 损伤反应途径的参与。在这项研究中，我们表明，病毒 E1 解旋酶与细胞 UAF1-USP1 复合物之间先前描述的相互作用对于双向复制的完成和随后单向复制机制的启动是必需的。我们的研究结果表明 HPV 可能利用细胞范可尼贫血 DNA 损伤途径来实现由双向θ复制产生的子分子的分离。此外，我们的结果表明 HPV 基因组的单向复制是从双向θ复制叉的重启动开始的。
