Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan.
Mol Cancer Res. 2009 Oct;7(10):1672-85. doi: 10.1158/1541-7786.MCR-09-0112. Epub 2009 Oct 6.
The mechanism responsible for hepatitis B virus (HBV) exacerbation during chemotherapy and radiotherapy remains unknown. We investigated whether the activation of DNA repair pathways influences HBV replication. The upregulation of the promyelocytic leukemia (PML) protein and its associated PML nuclear body (PML-NB) by chemotherapy and irradiation-induced DNA repair signaling correlated with the upregulation of HBV pregenomic transcription, HBV-core expression, and HBV DNA replication. The HBV-core protein and HBV DNA localized to PML-NBs, where they associated with PML and histone deacetylase 1 (HDAC1). Chemotherapy and radiotherapy affected the interactions between PML, HBV-core, and HDAC1. The enhanced protein-protein interaction between PML and HBV-core inhibited PML-mediated apoptosis and decreased PML-associated HDAC activity. The reversal of HDAC-mediated repression on the HBV covalently closed circular DNA basal core promoter resulted in the amplification of HBV-core and pregenomic expression. These results suggest that PML in PML-NBs links the DNA damage response with HBV replication and may cooperate with HBV-core and HDAC1 on the HBV covalently closed circular DNA basal core promoter to form a positive feedback loop for HBV exacerbation during chemotherapy and radiotherapy.
导致乙型肝炎病毒（HBV）在化疗和放疗期间恶化的机制尚不清楚。我们研究了 DNA 修复途径的激活是否会影响 HBV 复制。化学疗法和辐射诱导的 DNA 修复信号引起的早幼粒细胞白血病（PML）蛋白及其相关 PML 核体（PML-NB）的上调与 HBV 前基因组转录、HBV 核心表达和 HBV DNA 复制的上调相关。HBV 核心蛋白和 HBV DNA 定位于 PML-NBs，与 PML 和组蛋白去乙酰化酶 1（HDAC1）相关。化疗和放疗影响 PML、HBV 核心和 HDAC1 之间的相互作用。PML 和 HBV 核心之间增强的蛋白-蛋白相互作用抑制了 PML 介导的细胞凋亡，并降低了 PML 相关的 HDAC 活性。HDAC 介导的对 HBV 共价闭合环状 DNA 基本核心启动子的抑制作用的逆转导致 HBV 核心和前基因组表达的扩增。这些结果表明，PML-NBs 中的 PML 将 DNA 损伤反应与 HBV 复制联系起来，并且可能与 HBV 核心和 HDAC1 一起在 HBV 共价闭合环状 DNA 基本核心启动子上形成正反馈回路，从而导致化疗和放疗期间 HBV 的恶化。
