Lee Suk-Hee, Oshige Masahiko, Durant Stephen T, Rasila Kanwaldeep Kaur, Williamson Elizabeth A, Ramsey Heather, Kwan Lori, Nickoloff Jac A, Hromas Robert
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, USA.
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18075-80. doi: 10.1073/pnas.0503676102. Epub 2005 Dec 6.
The molecular mechanism by which foreign DNA integrates into the human genome is poorly understood yet critical to many disease processes, including retroviral infection and carcinogenesis, and to gene therapy. We hypothesized that the mechanism of genomic integration may be similar to transposition in lower organisms. We identified a protein, termed Metnase, that has a SET domain and a transposase/nuclease domain. Metnase methylates histone H3 lysines 4 and 36, which are associated with open chromatin. Metnase increases resistance to ionizing radiation and increases nonhomologous end-joining repair of DNA doublestrand breaks. Most significantly, Metnase promotes integration of exogenous DNA into the genomes of host cells. Therefore, Metnase is a nonhomologous end-joining repair protein that regulates genomic integration of exogenous DNA and establishes a relationship among histone modification, DNA repair, and integration. The data suggest a model wherein Metnase promotes integration of exogenous DNA by opening chromatin and facilitating joining of DNA ends. This study demonstrates that eukaryotic transposase domains can have important cell functions beyond transposition of genetic elements.
外源DNA整合到人类基因组中的分子机制目前仍知之甚少，但它对包括逆转录病毒感染、致癌作用以及基因治疗在内的许多疾病过程至关重要。我们推测基因组整合机制可能类似于低等生物中的转座作用。我们鉴定出一种名为Metnase的蛋白质，它具有一个SET结构域和一个转座酶/核酸酶结构域。Metnase使与开放染色质相关的组蛋白H3赖氨酸4和36发生甲基化。Metnase增强对电离辐射的抗性，并增加DNA双链断裂的非同源末端连接修复。最显著的是，Metnase促进外源DNA整合到宿主细胞基因组中。因此，Metnase是一种非同源末端连接修复蛋白，它调节外源DNA的基因组整合，并在组蛋白修饰、DNA修复和整合之间建立联系。这些数据提示了一个模型，其中Metnase通过打开染色质并促进DNA末端连接来促进外源DNA整合。这项研究表明，真核转座酶结构域除了具有遗传元件转座功能外，还能发挥重要的细胞功能。
