Human immunodeficiency virus type 1 Vpr-mediated G2 arrest requires Rad17 and Hus1 and induces nuclear BRCA1 and gamma-H2AX focus formation.
Human immunodeficiency virus type 1 Vpr-mediated G2 arrest requires Rad17 and Hus1 and induces nuclear BRCA1 and gamma-H2AX focus formation.
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人类免疫缺陷病毒 1 型 Vpr 介导的 G2 停滞需要 Rad17 和 Hus1，并诱导核 BRCA1 和 γ-H2AX 病灶形成。
DOI：
10.1128/mcb.24.21.9286-9294.2004
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发表时间：
2004
影响因子：
5.3
通讯作者：
Planelles,Vicente
中科院分区：
文献类型：
--
作者：
Zimmerman,ErikS;Chen,Junjie;Andersen,JoshuaL;Ardon,Orly;Dehart,JasonL;Blackett,Jana;Choudhary,ShaileshK;Camerini,David;Nghiem,Paul;Planelles,Vicente
真核细胞已经进化出一种复杂的机制来感知基因组复制过程中的DNA损伤。这一途径的激活阻止了进入有丝分裂，从而允许DNA修复，或者在发生不可修复的损伤时，致力于细胞凋亡。在复制应激条件下，损伤信号由共济失调-毛细血管扩张突变和Rad3相关的激酶ATR启动。我们最近证实，人类免疫缺陷病毒1型(HIV-1)基因产物病毒蛋白R(VPR)通过激活ATR将感染细胞滞留在G2期。在本研究中，我们证明了VPR激活ATR类似于某些遗传毒性物质的激活，无论是在机制上还是在其下游后果上。具体地说，我们发现Rad17和Hus1需要诱导G2停滞，以及VPR诱导组蛋白2A变异体X(H_2AX)的磷酸化和含有H_2AX和乳腺癌易感蛋白1的核形成。这些结果表明，由HIV-1基因产物VPR介导的G_2停滞利用了细胞信号通路，其生理功能是识别复制应激。这些发现将有助于更好地理解HIV-1在HIV-1致病过程中如何操纵CD4+淋巴细胞细胞周期和诱导细胞凋亡。
Eukaryotic cells have evolved a complex mechanism for sensing DNA damage during genome replication. Activation of this pathway prevents entry into mitosis to allow for either DNA repair or, in the event of irreparable damage, commitment to apoptosis. Under conditions of replication stress, the damage signal is initiated by the ataxia-telangiectasia-mutated and Rad3-related kinase ATR. We recently demonstrated that the human immunodeficiency virus type 1 (HIV-1) gene product viral protein R (Vpr) arrests infected cells in the G2phase via the activation of ATR. In the present study, we show that the activation of ATR by Vpr is analogous to activation by certain genotoxic agents, both mechanistically and in its downstream consequences. Specifically, we show a requirement for Rad17 and Hus1 to induce G2arrest as well as Vpr-induced phosphorylation of histone 2A variant X (H2AX) and formation of nuclear foci containing H2AX and breast cancer susceptibility protein 1. These results demonstrate that G2arrest mediated by the HIV-1 gene product Vpr utilizes the cellular signaling pathway whose physiological function is to recognize replication stress. These findings should contribute to a greater understanding of how HIV-1 manipulates the CD4+-lymphocyte cell cycle and apoptosis induction in the progressive CD4+-lymphocyte depletion characteristic of HIV-1 pathogenesis.