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美国科学家量身定制半合成生物

摘要 : 5月8日,一篇刊登于《自然》杂志的论文描述了一例能稳定包含“非自然”人造碱基DNA的半合成生物。通常,一个由两对碱基对(A和T,C和G)组成的“遗传字母表”构成了所有生命形式的DNA。而通过扩展遗传密码来包含非天然碱基对,可以开发出有实际应用价值的定制生物。
美国科学家量身定制半合成生物

5月8日,一篇刊登于《自然》杂志的论文描述了一例能稳定包含“非自然”人造碱基DNA的半合成生物。通常,一个由两对碱基对(A和T,C和G)组成的“遗传字母表”构成了所有生命形式的DNA。而通过扩展遗传密码来包含非天然碱基对,可以开发出有实际应用价值的定制生物。

美国加州拉霍亚斯克里普斯研究所Floyd Romesberg及其同事之前曾开发出一对非天然碱基对(d5SICSTP 和dNaMT),这对碱基对可以在一个纯净的无细胞系统中实现DNA复制过程。但把这个结果推衍到一个细胞中并非轻而易举,例如,如何把这些非自然的碱基对引导入细胞就是一个挑战。

在新研究中,研究人员展示了在拥有非天然碱基转运蛋白的大肠杆菌细胞中,这对非天然碱基可以在不明显影响细胞生长的情况下融合到一个正在复制的质粒中,完成质粒DNA的复制并且不会被DNA修复机制识别为异常。因此,该研究给一个生物体可以稳定地使用扩展遗传字母表进行复制提供了证据。

创建使用非天然核苷酸的新生物一直是合成生物学的目标。这样的生物可以为很多细胞工程(使用非天然氨基酸合成新蛋白)提供平台。

另外,相关人士在分析合成生物学领域所面临的最大挑战的同时,还调查了该领域中渴望专利和支持所有内容免费开放两方之间的摩擦。与此同时,一组合成生物领域的专家呼吁应让在哺乳动物中的更多研究能经受住演化的设计。

原文摘要:

A semi-synthetic organism with an expanded genetic alphabet

Denis A. Malyshev, Kirandeep Dhami, Thomas Lavergne, Tingjian Chen, Nan Dai, Jeremy M. Foster, Ivan R. Corrêa & Floyd E. Romesberg

Organisms are defined by the information encoded in their genomes, and since the origin of life this information has been encoded using a two-base-pair genetic alphabet (A–T and G–C). In vitro, the alphabet has been expanded to include several unnatural base pairs (UBPs). We have developed a class of UBPs formed between nucleotides bearing hydrophobic nucleobases, exemplified by the pair formed between d5SICS and dNaM (d5SICS–dNaM), which is efficiently PCR-amplified and transcribed in vitro, and whose unique mechanism of replication has been characterized. However, expansion of an organism’s genetic alphabet presents new and unprecedented challenges: the unnatural nucleoside triphosphates must be available inside the cell; endogenous polymerases must be able to use the unnatural triphosphates to faithfully replicate DNA containing the UBP within the complex cellular milieu; and finally, the UBP must be stable in the presence of pathways that maintain the integrity of DNA. Here we show that an exogenously expressed algal nucleotide triphosphate transporter efficiently imp0rts the triphosphates of both d5SICS and dNaM (d5SICSTP and dNaMTP) into Escherichia coli, and that the endogenous replication machinery uses them to accurately replicate a plasmid containing d5SICS–dNaM. Neither the presence of the unnatural triphosphates nor the replication of the UBP introduces a notable growth burden. Lastly, we find that the UBP is not efficiently excised by DNA repair pathways. Thus, the resulting bacterium is the first organism to propagate stably an expanded genetic alphabet.

对应Nature杂志: 2014年5月15日Nature杂志精选

来源: 中国科学报 浏览次数:330

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