Epstein-Barr virus (EBV) is an oncogenic herpesvirus and WHO class 1 carcinogen that resides in B lymphocytes of nearly all humans. While silent in most, EBV can cause endemic Burkitt lymphoma in children and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. The pathogenesis of such lymphomas is multifactorial but to a large extent depends on EBV's ability to aggressively drive cellular DNA replication and B cell proliferation despite cell-intrinsic barriers to replication. One such barrier is oncogenic replication stress which hinders the progression of DNA replication forks. To understand how EBV successfully overcomes replication stress, we examined cellular replication forks in EBV-transformed B cells using iPOND (isolation of Proteins on Nascent DNA)-mass spectrometry and identified several cellular proteins that had not previously been linked to DNA replication. Of eight candidate replisome-associated proteins that we validated at forks in EBV-transformed cells and Burkitt lymphoma-derived cells, three zinc finger proteins (ZFPs) were upregulated early in B cells newly-infected with EBV in culture as well as expressed at high levels in EBV-infected B blasts in the blood of immunocompromised transplant recipients. Expressed highly in S- and G2-phase cells, knockdown of each ZFP resulted in stalling of proliferating cells in the S-phase, cleavage of caspase 3, and cell death. These proteins, newly-identified at replication forks of EBV-transformed and Burkitt lymphoma cells therefore contribute to cell survival and cell cycle progression, and represent novel targets for intervention of EBV-lymphomas while simultaneously offering a window into how the replication machinery may be similarly modified in other cancers.

中文翻译：

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EBV转化的B淋巴细胞中细胞复制叉处的新型复制子相关蛋白。

爱泼斯坦-巴尔病毒（EBV）是一种致癌性疱疹病毒，是世界卫生组织1类致癌物，几乎存在于所有人类的B淋巴细胞中。尽管在大多数情况下沉默，EBV可以引起儿童地方性Burkitt淋巴瘤和免疫受损宿主的移植后淋巴增生性疾病/淋巴瘤。此类淋巴瘤的发病机制是多因素的，但在很大程度上取决于EBV主动驱动细胞DNA复制和B细胞增殖的能力，尽管存在细胞内在的复制障碍。一种这样的障碍是致癌复制应激，其阻碍了DNA复制叉的发展。要了解EBV如何成功克服复制压力，我们使用iPOND-质谱分析了EBV转化的B细胞中的细胞复制叉，并鉴定了以前未与DNA复制相关的几种细胞蛋白。在我们在EBV转化的细胞和Burkitt淋巴瘤衍生的细胞中通过分叉验证的八种候选复制体相关蛋白中，三种锌指蛋白（ZFP）在新感染了EBV的B细胞中早期被上调，并在高表达下表达。免疫受损的移植受者血液中被EBV感染的B母细胞中的血红蛋白水平。在S期和G2期细胞中高度表达，每个ZFP的敲低导致S期增殖细胞的停滞，胱天蛋白酶3的裂解和细胞死亡。这些蛋白质，