Limited nucleotide pools restrict Epstein-Barr virus-mediated B-cell immortalization.
Limited nucleotide pools restrict Epstein-Barr virus-mediated B-cell immortalization.
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DOI：
10.1038/oncsis.2017.46
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发表时间：
2017-06-12
期刊：
影响因子：
6.2
通讯作者：
Luftig MA
中科院分区：
文献类型：
--
作者：
Hafez AY;Messinger JE;McFadden K;Fenyofalvi G;Shepard CN;Lenzi GM;Kim B;Luftig MA
细胞癌基因的激活以及肿瘤病毒的感染可以促进宿主DNA损伤反应的异常增殖和激活。原代人B细胞的EB病毒（EBV）感染诱导短暂的过度增殖期，但这些感染的细胞中的许多B细胞屈服于共济失调毛细血管扩张突变/检查点激酶2（ATM/Chk 2）介导的衰老样生长停滞。在这项研究中，我们评估了DNA复制应激和核苷酸库水平在限制EBV感染的B细胞生长中的作用。我们发现，EBV触发激活共济失调毛细血管扩张和Rad 3相关（ATR）信号通路在早期快速增殖细胞，这也是显着更敏感的ATR通路的抑制比晚期衰减增殖细胞。通过核晕分析，我们确定，早期EBV感染的细胞显示相对于晚期增殖细胞增加的复制应激和DNA损伤。最后，我们发现，感染后早期，过度增殖的B细胞表现出有限的脱氧核糖核苷酸三磷酸（dNTP）池相比，晚期增殖和EB病毒永生化的淋巴母细胞样细胞系的嘌呤dNTP的特定损失。重要的是，在过度增殖期之前补充外源性核苷显著增强了EBV引起的B细胞永生化，并挽救了复制应激。总之，我们的研究结果表明，嘌呤dNTP生物合成在EBV介导的B细胞永生化的早期阶段具有关键作用。
Activation of cellular oncogenes as well as infection with tumor viruses can promote aberrant proliferation and activation of the host DNA damage response. Epstein–Barr virus (EBV) infection of primary human B cells induces a transient period of hyper-proliferation, but many of these infected cells succumb to an ataxia telangiectasia mutated/checkpoint kinase 2 (ATM/Chk2)-mediated senescence-like growth arrest. In this study, we assessed the role of DNA replicative stress and nucleotide pool levels in limiting EBV-infected B-cell outgrowth. We found that EBV triggered activation of the ataxia telangiectasia and Rad3-related (ATR) signaling pathway in the early rapidly proliferating cells, which were also significantly more sensitive to inhibition of the ATR pathway than late attenuated proliferating cells. Through nuclear halo assays, we determined that early EBV-infected cells displayed increased replicative stress and DNA damage relative to late proliferating cells. Finally, we found that early after infection, hyper-proliferating B cells exhibited limited deoxyribonucleotide triphosphate (dNTP) pools compared with late proliferating and EBV-immortalized lymphoblastoid cell lines with a specific loss of purine dNTPs. Importantly, supplementation with exogenous nucleosides before the period of hyper-proliferation markedly enhanced B-cell immortalization by EBV and rescued replicative stress. Together our results suggest that purine dNTP biosynthesis has a critical role in the early stages of EBV-mediated B-cell immortalization.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
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通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
16
作者：
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通讯作者：
Zou L
影响因子：
11.2
作者：
Gilad O;Nabet BY;Ragland RL;Schoppy DW;Smith KD;Durham AC;Brown EJ
通讯作者：
Brown EJ