ATM-mediated DNA double-strand break response facilitated oncolytic Newcastle disease virus replication and promoted syncytium formation in tumor cells
ATM-mediated DNA double-strand break response facilitated oncolytic Newcastle disease virus replication and promoted syncytium formation in tumor cells
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ATM介导的DNA双链断裂反应促进溶瘤新城疫病毒复制并促进肿瘤细胞合胞体形成
DOI：
10.1371/journal.ppat.1008514
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发表时间：
2020-06
期刊：
影响因子：
6.7
通讯作者：
Ding Chan
中科院分区：
文献类型：
--
作者：
Ren Shanhui;Rehman Zaib Ur;Gao Bo;Yang Zengqi;Zhou Jiyong;Meng Chunchun;Song Cuiping;Nair Venugopal;Sun Yingjie;Ding Chan
脱氧核糖核酸（DNA）损伤反应（DDR）是维持基因组完整性和抑制肿瘤发生的基本细胞反应。共济失调毛细血管扩张突变（ATM）激酶的激活是DNA双链断裂（DSB）的核心，用于维持哺乳动物细胞中宿主基因组的完整性。溶瘤性纽卡斯尔病病毒（NDV）能在肿瘤细胞中选择性复制，但其对肿瘤细胞基因组完整性的影响尚不清楚。在这里，我们发现膜融合和NDV感染触发了肿瘤细胞中的DSB。NDV的晚期复制和膜融合通过ATM-Chk 2轴机械地激活ATM介导的DSB途径，如DSB的标志所证明的，即，自磷酸化ATM和磷酸化H2 AX和Chk 2。免疫荧光数据显示，多方面的ATM控制的磷酸化显着诱导响应NDV感染和F-HN共表达的泛核泪点灶的形成。对ATM激酶活性的特异性药物抑制实验进一步表明，ATM介导的DSB促进NDV复制和膜融合。我们证实了Mre 11-RAD 50-NBS 1（MRN）复合物感知由NDV感染和膜融合触发的DSB信号激活。药理学抑制MRN活性也显著抑制细胞内和细胞外NDV复制和合胞体形成。总的来说，这些数据首次确定了由病毒感染诱导的膜融合与DDR途径之间的直接联系，从而为溶瘤NDV在肿瘤细胞中的有效复制提供了新的见解。
Deoxyribonucleic acid (DNA) damage response (DDR) is the fundamental cellular response for maintaining genomic integrity and suppressing tumorigenesis. The activation of ataxia telangiectasia-mutated (ATM) kinase is central to DNA double-strand break (DSB) for maintaining host-genome integrity in mammalian cells. Oncolytic Newcastle disease virus (NDV) can selectively replicate in tumor cells; however, its influence on the genome integrity of tumor cells is not well-elucidated. Here, we found that membrane fusion and NDV infection triggered DSBs in tumor cells. The late replication and membrane fusion of NDV mechanistically activated the ATM-mediated DSB pathway via the ATM-Chk2 axis, as evidenced by the hallmarks of DSBs, i.e., auto-phosphorylated ATM and phosphorylated H2AX and Chk2. Immunofluorescence data showed that multifaceted ATM-controlled phosphorylation markedly induced the formation of pan-nuclear punctum foci in response to NDV infection and F-HN co-expression. Specific drug-inhibitory experiments on ATM kinase activity further suggested that ATM-mediated DSBs facilitated NDV replication and membrane fusion. We confirmed that the Mre11-RAD50-NBS1 (MRN) complex sensed the DSB signal activation triggered by NDV infection and membrane fusion. The pharmacological inhibition of MRN activity also significantly inhibited intracellular and extracellular NDV replication and syncytia formation. Collectively, these data identified for the first time a direct link between the membrane fusion induced by virus infection and DDR pathways, thereby providing new insights into the efficient replication of oncolytic NDV in tumor cells.
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DOI：
10.1042/bj20080413
发表时间：
2009-02-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Mahaney BL;Meek K;Lees-Miller SP
通讯作者：
Lees-Miller SP
影响因子：
6.7
作者：
Lilley CE;Chaurushiya MS;Boutell C;Everett RD;Weitzman MD
通讯作者：
Weitzman MD
影响因子：
5.4
作者：
Luo, Yong;Chen, Aaron Yun;Qiu, Jianming
通讯作者：
Qiu, Jianming
影响因子：
11.4
作者：
Uziel, T;Lerenthal, Y;Shiloh, Y
通讯作者：
Shiloh, Y
影响因子：
9.2
作者：
Paull, TT;Rogakou, EP;Bonner, WM
通讯作者：
Bonner, WM