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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >APOBEC3G hypermutates genomic DNA and inhibits Ty1 retrotransposition in yeast
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APOBEC3G hypermutates genomic DNA and inhibits Ty1 retrotransposition in yeast

机译：APOBEC3G突变基因组DNA并抑制酵母中Ty1逆转座

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摘要

Human cells harbor a variety of factors that function to block the proliferation of foreign nucleic acid. The APOBEC3G enzyme inhibits the replication of retroviruses by deaminating nascent retroviral cDNA cytosines to uracils, lesions that can result in lethal levels of hypermutation. Here, we demonstrate that APOBEC3G is capable of deaminating genomic cytosines in Saccharomyces cerevisiae. APOBEC3G expression caused a 20-fold increase in frequency of mutation to canavanine-resistance, which was further elevated in a uracil DNA glycosylase-deficient background. All APOBEC3G-induced base substitution mutations mapped to the nuclear CAN1 gene and were exclusively C/G -> T/A transition mutations within a 5'-CC consensus. The APOBEC3G preferred sites were found on both strands of the DNA duplex, but were otherwise located in hotspots nearly identical to those found previously in retroviral cDNA. This unique genetic system further enabled us to show that expression of APOBEC3G or its homolog APOBEC3F was able to inhibit the mobility of the retrotransposon Ty1 by a mechanism that involves the deamination of cDNA cytosines. Thus, these data expand the range of likely APOBEC3 targets to include nuclear DNA and endogenous retroelements, which have pathological and physiological implications, respectively. We postulate that the APOBEC3-dependent innate cellular defense constitutes a tightly regulated arm of a conserved mobile nucleic acid restriction mechanism that is poised to limit internal as well as external assaults.
机译：人细胞具有多种功能，可阻止外来核酸的增殖。 APOBEC3G酶通过将新生的逆转录病毒cDNA胞嘧啶脱氨为尿嘧啶来抑制逆转录病毒的复制，这些损伤可导致致命的超突变水平。在这里，我们证明了APOBEC3G能够消除酿酒酵母中的基因组胞嘧啶。 APOBEC3G的表达引起对卡那万碱抗性的突变频率增加了20倍，而在尿嘧啶DNA糖基化酶缺乏的背景下，该频率进一步升高。所有APOBEC3G诱导的碱基取代突变都映射到核CAN1基因，并且在5'-CC共识内完全是C / G→T / A过渡突变。在DNA双链体的两条链上都发现了APOBEC3G的优选位点，但位于与以前在逆转录病毒cDNA中发现的热点几乎相同的热点中。这个独特的遗传系统进一步使我们能够证明，APOBEC3G或其同源物APOBEC3F的表达能够通过涉及cDNA胞嘧啶脱氨基的机制抑制逆转录转座子Ty1的迁移。因此，这些数据扩大了可能的APOBEC3靶标的范围，使其包括核DNA和内源逆转录酶，它们分别具有病理学和生理学意义。我们假设依赖APOBEC3的先天细胞防御构成了保守的移动核酸限制机制的严格调节臂，该机制有望限制内部和外部攻击。

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