Department of Biochemistry, Molecular Biology and Biophysics, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, USA.
Nat Struct Mol Biol. 2010 Feb;17(2):222-9. doi: 10.1038/nsmb.1744. Epub 2010 Jan 10.
Bacteria evolved restriction endonucleases to prevent interspecies DNA transmission and bacteriophage infection. Here we show that human cells possess an analogous mechanism. APOBEC3A is induced by interferon following DNA detection, and it deaminates foreign double-stranded DNA cytidines to uridines. These atypical DNA nucleosides are converted by the uracil DNA glycosylase UNG2 to abasic lesions, which lead to foreign DNA degradation. This mechanism is evident in cell lines and primary monocytes, where up to 97% of cytidines in foreign DNA are deaminated. In contrast, cellular genomic DNA appears unaffected. Several other APOBEC3s also restrict foreign gene transfer. Related proteins exist in all vertebrates, indicating that foreign DNA restriction may be a conserved innate immune defense mechanism. The efficiency and fidelity of genetic engineering, gene therapy, and DNA vaccination are likely to be influenced by this anti-DNA defense system.
细菌进化出限制内切酶来防止种间 DNA 传递和噬菌体感染。在这里，我们表明人类细胞拥有类似的机制。APOBEC3A 在 DNA 检测后被干扰素诱导，它使外来双链 DNA 的胞嘧啶脱氨基成为尿嘧啶。这些非典型的 DNA 核苷被尿嘧啶 DNA 糖基化酶 UNG2 转化为碱基缺失损伤，导致外来 DNA 的降解。该机制在细胞系和原代单核细胞中都很明显，其中多达 97%的外来 DNA 胞嘧啶被脱氨基。相比之下，细胞基因组 DNA 似乎没有受到影响。其他几种 APOBEC3 也限制了外源基因的转移。相关蛋白存在于所有脊椎动物中，表明外源 DNA 限制可能是一种保守的先天免疫防御机制。基因工程、基因治疗和 DNA 疫苗的效率和保真度可能会受到这种抗 DNA 防御系统的影响。
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