HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination
HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination
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DOI：
10.1038/sj.onc.1209831
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发表时间：
2007-01-25
期刊：
影响因子：
8
通讯作者：
Ishizaka, Y.
中科院分区：
文献类型：
--
作者：
Nakai-Murakami, C.;Shimura, M.;Ishizaka, Y.
ATM 依赖性细胞信号，即 DNA 损伤反应，已被证明与 1 型人类免疫缺陷病毒 (HIV-1) 感染有关，并且在 HIV-1 阳性患者中观察到恶性肿瘤发展的高发生率。 Vpr 是 HIV-1 的辅助基因产物，可延迟 G2/M 期细胞周期的进展，而另一种 DNA 损伤信号 ATR-Chk1-Wee-1 是负责 Vpr 诱导的细胞周期停滞的细胞途径。在这项研究中，我们提供的证据表明 Vpr 还可以激活 ATM，并诱导 γ-H2AX 的表达和 Chk2 的磷酸化。引人注目的是，Vpr 被发现可以刺激 Rad51 和 BRCA1 的焦点形成，这两种蛋白参与通过同源重组修复 DNA 双链断裂 (DSB) (1411)，并且生化分析表明，Vpr 解离了染色质部分中 p53 和 Rad51 的相互作用，正如在辐射诱导的 DSB 下观察到的那样。人们一致发现，Vpr 可以提高 I-Scel 位点的 HR 率，I-Scel 是一种引入基因组的罕见切割酶位点。 Vpr 增强的 HR 速率增加被 ATM 抑制剂 KU55933 减弱，这表明 Vpr 诱导的 DSB 激活 ATM 依赖性细胞信号，从而增强细胞内重组潜力。根据最近的一份报告，KU55933 减弱了 HIV-1 整合到宿主基因组中的能力，我们讨论了 Vpr 诱导的 DSB 在病毒整合以及 HIV-1 相关恶性肿瘤中的可能作用。
An ATM-dependent cellular signal, a DNA-damage response, has been shown to be involved during infection of human immunodeficiency virus type-1 (HIV-1), and a high incidence of malignant tumor development has been observed in HIV-1-positive patients. Vpr, an accessory gene product of HIV-1, delays the progression of the cell cycle at the G2/M phase, and ATR-Chk1-Wee-1, another DNA-damage signal, is a proposed cellular pathway responsible for the Vpr-induced cell cycle arrest. In this study, we present evidence that Vpr also activates ATM, and induces expression of gamma-H2AX and phosphorylation of Chk2. Strikingly, Vpr was found to stimulate the focus formation of Rad51 and BRCA1, which are involved in repair of DNA double-strand breaks (DSBs) by homologous recombination (1411), and biochemical analysis revealed that Vpr dissociates the interaction of p53 and Rad51 in the chromatin fraction, as observed under irradiation-induced DSBs. Vpr was consistently found to increase the rate of HR in the locus of I-Scel, a rare cutting-enzyme site that had been introduced into the genome. An increase of the HR rate enhanced by Vpr was attenuated by an ATM inhibitor, KU55933, suggesting that Vpr-induced DSBs activate ATM-dependent cellular signal that enhances the intracellular recombination potential. In context with a recent report that KU55933 attenuated the integration of HIV-1 into host genomes, we discuss the possible role of Vpr-induced DSBs in viral integration and also in HIV-1 associated malignancy.