HIV-1 Vpr induces DNA double-strand breaks.
HIV-1 Vpr induces DNA double-strand breaks.
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DOI：
10.1158/0008-5472.can-05-3144
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发表时间：
2006-01
期刊：
影响因子：
11.2
通讯作者：
H. Tachiwana;M. Shimura;Chikako Nakai-Murakami;K. Tokunaga;Y. Takizawa;T. Sata;H. Kurumizaka;Y. Ish
中科院分区：
文献类型：
--
作者：
H. Tachiwana;M. Shimura;Chikako Nakai-Murakami;K. Tokunaga;Y. Takizawa;T. Sata;H. Kurumizaka;Y. Ish
最近的观察表明，HIV-1感染诱导了染色体DNA损伤反应。然而，其确切的分子机制和生物学相关性尚不完全清楚。在这里，我们报告了HIV-1感染导致染色体DNA双链断裂。我们进一步发现，HIV-1的辅助基因产物vpr是导致HIV-1诱导双链断裂的主要因素。纯化的VPR蛋白在与分离的核孵育时促进双链断裂，尽管它在体外不显示核酸内切酶活性。DNA结合活性缺陷的羧基末端截短的VPR突变体在分离的核中形成依赖于VPR的双链断裂的能力较低。提示vpr引起的双链断裂依赖于其与DNA的结合活性，vpr可能将具有核酸内切酶阳性活性的未知核因子S募集到染色体DNA中。这是VPR诱导HIV-1感染细胞双链断裂的第一个直接证据。我们讨论了VPR诱导的DNA损伤在HIV-1感染中的可能作用，以及VPR在进一步的获得性免疫缺陷综合征相关肿瘤发展中的参与。
Recent observations imply that HIV-1 infection induces chromosomal DNA damage responses. However, the precise molecular mechanism and biological relevance are not fully understood. Here, we report that HIV-1 infection causes double-strand breaks in chromosomal DNA. We further found that Vpr, an accessory gene product of HIV-1, is a major factor responsible for HIV-1-induced double-strand breaks. The purified Vpr protein promotes double-strand breaks when incubated with isolated nuclei, although it does not exhibit endonuclease activity in vitro. A carboxyl-terminally truncated Vpr mutant that is defective in DNA-binding activity is less capable of Vpr-dependent double-strand break formation in isolated nuclei. The data suggest that double-strand breaks induced by Vpr depend on its DNA-binding activity and that Vpr may recruit unknown nuclear factor(s) with positive endonuclease activity to chromosomal DNA. This is the first direct evidence that Vpr induces double-strand breaks in HIV-1-infected cells. We discuss the possible roles of Vpr-induced DNA damage in HIV-1 infection and the involvement of Vpr in further acquired immunodeficiency syndrome-related tumor development.