PARP1 Stabilizes CTCF Binding and Chromatin Structure To Maintain Epstein-Barr Virus Latency Type.
PARP1 Stabilizes CTCF Binding and Chromatin Structure To Maintain Epstein-Barr Virus Latency Type.
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DOI：
10.1128/jvi.00755-18
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发表时间：
2018-09-15
影响因子：
5.4
通讯作者：
Tempera I
中科院分区：
文献类型：
--
作者：
Lupey-Green LN;Caruso LB;Madzo J;Martin KA;Tan Y;Hulse M;Tempera I
EBV是一种人类γ疱疹病毒，感染全球95%以上的个体。感染后，EBV作为附加体环化并在B细胞中建立慢性潜伏感染。在这样做时，病毒利用宿主细胞机制来调节和维持病毒基因组。在其他健康的个体中，EBV感染通常是非病理性的;然而，潜伏感染是潜在的致癌性的，并导致1%的人类癌症。在潜伏感染期间，EBV根据给定的潜伏类型表达特定的蛋白质组，每种蛋白质与特定类型的癌症相关。例如，III型潜伏期，其中病毒表达其全部潜伏蛋白，是与EBV感染相关的AIDS相关和移植后淋巴瘤的特征。了解病毒潜伏类型如何在染色质水平上调节，可能会揭示EBV相关癌症中EBV特异性药物干预的潜在靶点。爱泼斯坦巴尔病毒（EBV）是一种潜在致癌的γ疱疹病毒，其在记忆B细胞中建立慢性潜伏感染。EBV基因组作为染色质化的附加体存在于感染的宿主细胞中，并受到染色质介导的调节。宿主绝缘子蛋白CTCF与EBV基因组的结合在维持病毒潜伏类型中具有确定的作用。CTCF被宿主酶PARP 1翻译后修饰。PARP 1或聚（ADP-核糖）聚合酶1催化聚（ADP-核糖）（PAR）部分从NAD+转移到受体蛋白上，包括其自身、组蛋白和CTCF。PARP 1对CTCF的PAR化可以影响CTCF的绝缘子活性、DNA结合能力和形成染色质环的能力。PARP 1和CTCF都参与了EBV潜伏期和裂解性再激活的调节。因此，我们预测PARP 1抑制剂的药理学抑制作用将通过染色质特异性机制影响EBV潜伏类型。在这里，我们表明，PARP 1和CTCF共定位在特定的网站在整个EBV基因组，并提供证据表明，PARP 1的行为，以稳定CTCF结合，并保持开放的染色质景观在活性Cp启动子在III型潜伏期。此外，PARP 1活性在维持潜伏型特异性病毒基因表达中是重要的。本文提供的数据为使用PARP抑制剂治疗表现出III型潜伏期的EBV相关癌症提供了依据，并最终可能有助于AIDS相关或移植后淋巴瘤的EBV特异性治疗策略。重要信息EBV是一种人类γ疱疹病毒，感染全球95%以上的个体。感染后，EBV作为附加体环化并在B细胞中建立慢性潜伏感染。在这样做时，病毒利用宿主细胞机制来调节和维持病毒基因组。在其他健康的个体中，EBV感染通常是非病理性的;然而，潜伏感染是潜在的致癌性的，并导致1%的人类癌症。在潜伏感染期间，EBV根据给定的潜伏类型表达特定的蛋白质组，每种蛋白质与特定类型的癌症相关。例如，III型潜伏期，其中病毒表达其全部潜伏蛋白，是与EBV感染相关的AIDS相关和移植后淋巴瘤的特征。了解病毒潜伏类型如何在染色质水平上调节，可能会揭示EBV相关癌症中EBV特异性药物干预的潜在靶点。
EBV is a human gammaherpesvirus that infects more than 95% of individuals worldwide. Upon infection, EBV circularizes as an episome and establishes a chronic, latent infection in B cells. In doing so, the virus utilizes host cell machinery to regulate and maintain the viral genome. In otherwise healthy individuals, EBV infection is typically nonpathological; however, latent infection is potentially oncogenic and is responsible for 1% of human cancers. During latent infection, EBV expresses specific sets of proteins according to the given latency type, each of which is associated with specific types of cancers. For example, type III latency, in which the virus expresses its full repertoire of latent proteins, is characteristic of AIDS-associated and posttransplant lymphomas associated with EBV infection. Understanding how viral latency type is regulated at the chromatin level may reveal potential targets for EBV-specific pharmacological intervention in EBV-associated cancers. Epstein Barr virus (EBV) is a potentially oncogenic gammaherpesvirus that establishes a chronic, latent infection in memory B cells. The EBV genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type. CTCF is posttranslationally modified by the host enzyme PARP1. PARP1, or poly(ADP-ribose) polymerase 1, catalyzes the transfer of a poly(ADP-ribose) (PAR) moiety from NAD+ onto acceptor proteins, including itself, histone proteins, and CTCF. PARylation of CTCF by PARP1 can affect CTCF's insulator activity, DNA binding capacity, and ability to form chromatin loops. Both PARP1 and CTCF have been implicated in the regulation of EBV latency and lytic reactivation. Thus, we predicted that pharmacological inhibition with PARP1 inhibitors would affect EBV latency type through a chromatin-specific mechanism. Here, we show that PARP1 and CTCF colocalize at specific sites throughout the EBV genome and provide evidence to suggest that PARP1 acts to stabilize CTCF binding and maintain the open chromatin landscape at the active Cp promoter during type III latency. Further, PARP1 activity is important in maintaining latency type-specific viral gene expression. The data presented here provide a rationale for the use of PARP inhibitors in the treatment of EBV-associated cancers exhibiting type III latency and ultimately could contribute to an EBV-specific treatment strategy for AIDS-related or posttransplant lymphomas. IMPORTANCE EBV is a human gammaherpesvirus that infects more than 95% of individuals worldwide. Upon infection, EBV circularizes as an episome and establishes a chronic, latent infection in B cells. In doing so, the virus utilizes host cell machinery to regulate and maintain the viral genome. In otherwise healthy individuals, EBV infection is typically nonpathological; however, latent infection is potentially oncogenic and is responsible for 1% of human cancers. During latent infection, EBV expresses specific sets of proteins according to the given latency type, each of which is associated with specific types of cancers. For example, type III latency, in which the virus expresses its full repertoire of latent proteins, is characteristic of AIDS-associated and posttransplant lymphomas associated with EBV infection. Understanding how viral latency type is regulated at the chromatin level may reveal potential targets for EBV-specific pharmacological intervention in EBV-associated cancers.