Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bld 4-131, 4 Center Drive, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2461-6. doi: 10.1073/pnas.0911128107. Epub 2010 Jan 21.
The cellular transcriptional coactivator HCF-1 interacts with numerous transcription factors as well as other coactivators and is a component of multiple chromatin modulation complexes. The protein is essential for the expression of the immediate early genes of both herpes simplex virus (HSV) and varicella zoster virus and functions, in part, by coupling chromatin modification components including the Set1 or MLL1 histone methyltransferases and the histone demethylase LSD1 to promote the installation of positive chromatin marks and the activation of viral immediately early gene transcription. Although studies have investigated the role of HCF-1 in both cellular and viral transcription, little is known about other processes that the protein may be involved in. Here we demonstrate that HCF-1 localizes to sites of HSV replication late in infection. HCF-1 interacts directly and simultaneously with both HSV DNA replication proteins and the cellular histone chaperone Asf1b, a protein that regulates the progression of cellular DNA replication forks via chromatin reorganization. Asf1b localizes with HCF-1 in viral replication foci and depletion of Asf1b results in significantly reduced viral DNA accumulation. The results support a model in which the transcriptional coactivator HCF-1 is a component of the HSV DNA replication assembly and promotes viral DNA replication by coupling Asf1b to DNA replication components. This coupling provides a novel function for HCF-1 and insights into the mechanisms of modulating chromatin during DNA replication.
细胞转录共激活因子 HCF-1 与许多转录因子以及其他共激活因子相互作用，是多个染色质调节复合物的组成部分。该蛋白对于单纯疱疹病毒 (HSV) 和水痘带状疱疹病毒的即刻早期基因的表达是必需的，其部分功能是将染色质修饰成分（包括 Set1 或 MLL1 组蛋白甲基转移酶和组蛋白去甲基化酶 LSD1）与瞬时早期基因转录的激活相偶联，以促进正染色质标记的安装。尽管研究已经调查了 HCF-1 在细胞和病毒转录中的作用，但对于该蛋白可能参与的其他过程知之甚少。在这里，我们证明 HCF-1 在感染后期定位于 HSV 复制的部位。HCF-1 与 HSV DNA 复制蛋白和细胞组蛋白伴侣 Asf1b 直接且同时相互作用，Asf1b 通过染色质重排调节细胞 DNA 复制叉的进展。Asf1b 与 HCF-1 在病毒复制焦点中定位，Asf1b 的耗竭导致病毒 DNA 积累显著减少。结果支持这样一种模型，即转录共激活因子 HCF-1 是 HSV DNA 复制组装的组成部分，通过将 Asf1b 与 DNA 复制成分偶联来促进病毒 DNA 复制。这种偶联为 HCF-1 提供了一个新的功能，并深入了解了在 DNA 复制过程中调节染色质的机制。
