Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
Nucleic Acids Res. 2024 Jun 10;52(10):5451-5464. doi: 10.1093/nar/gkae355.
The emergence of RNA on the early Earth is likely to have been influenced by chemical and physical processes that acted to filter out various alternative nucleic acids. For example, UV photostability is thought to have favored the survival of the canonical nucleotides. In a recent proposal for the prebiotic synthesis of the building blocks of RNA, ribonucleotides share a common pathway with arabino- and threo-nucleotides. We have therefore investigated non-templated primer extension with 2-aminoimidazole-activated forms of these alternative nucleotides to see if the synthesis of the first oligonucleotides might have been biased in favor of RNA. We show that non-templated primer extension occurs predominantly through 5'-5' imidazolium-bridged dinucleotides, echoing the mechanism of template-directed primer extension. Ribo- and arabino-nucleotides exhibited comparable rates and yields of non-templated primer extension, whereas threo-nucleotides showed lower reactivity. Competition experiments confirmed the bias against the incorporation of threo-nucleotides. The incorporation of an arabino-nucleotide at the end of the primer acts as a chain terminator and blocks subsequent extension. These biases, coupled with potentially selective prebiotic synthesis, and the templated copying that is known to favour the incorporation of ribonucleotides, provide a plausible model for the effective exclusion of arabino- and threo-nucleotides from primordial oligonucleotides.
早期地球上 RNA 的出现可能受到了化学和物理过程的影响，这些过程起到了筛选各种替代核酸的作用。例如，UV 光稳定性被认为有利于规范核苷酸的存活。在最近提出的 RNA 构建块的前生物合成中，核糖核苷酸与阿拉伯糖核苷酸和苏糖核苷酸共享共同途径。因此，我们研究了这些替代核苷酸的无模板引物延伸，以了解第一个寡核苷酸的合成是否可能偏向 RNA。我们表明，无模板引物延伸主要通过 5'-5' 咪唑鎓桥联二核苷酸发生，这反映了模板指导的引物延伸机制。核糖核苷酸和阿拉伯糖核苷酸表现出可比的无模板引物延伸速率和产率，而苏糖核苷酸的反应性较低。竞争实验证实了对苏糖核苷酸掺入的偏见。在引物的末端掺入阿拉伯糖核苷酸充当链终止子并阻止随后的延伸。这些偏见，加上潜在的选择性前生物合成，以及已知有利于核糖核苷酸掺入的模板复制，为有效排除原始寡核苷酸中的阿拉伯糖核苷酸和苏糖核苷酸提供了一个合理的模型。
