A synthetic molecular system capable of mirror-image genetic replication and transcription

Abstract

The overwhelmingly homochiral nature of life has left a puzzle as to whether mirror-image biological systems based on a chirally inverted version of molecular machinery could also have existed. Here we report that two key steps in the central dogma of molecular biology, the template-directed polymerization of DNA and transcription into RNA, can be catalysed by a chemically synthesized D-amino acid polymerase on an L-DNA template. We also show that two chirally mirrored versions of the 174-residue African swine fever virus polymerase X could operate in a racemic mixture without significant enantiomeric cross-inhibition to the activity of each other. Furthermore, we demonstrate that a functionally active L-DNAzyme could be enzymatically produced using the D-amino acid polymerase. The establishment of such molecular systems with an opposite handedness highlights the potential to exploit enzymatically produced mirror-image biomolecules as research and therapeutic tools.

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Figure 1: Two chirally mirrored polymerase systems with synthetic L- and D-ASFV pol X.
Figure 2: Template-directed DNA polymerization by synthetic L- and D-ASFV pol X.
Figure 3: Polymerization of the two chirally mirrored systems in a racemic mixture.
Figure 4: Enzymatic polymerization of a mirror-image DNAzyme of active functions.
Figure 5: DNA-templated polymerization of mirror-image RNA.

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Acknowledgements

We thank Y. Shi, J. W. Szostak and N. Yan for helpful discussions and comments on the manuscript. We also thank Z. Chen, D. Li, Q. Li, P. Liang, X. Sheng, L. Sun, P. Yin and P. Xu for assistance with the recombinant ASFV pol X purification and isotope-labelling experiments, J. Liu and H. Deng for assistance with the MS experiments and Z. Li and X. Tao for assistance with the preparation of Fig. 1a. This work was supported in part by funding from the National Natural Science Foundation of China (grant no. 31470532, grant no. 91543102 and grant no. 21532004), the Ministry of Science and Technology of China (grant no. 2015CB553402 and grant no. 2013CB932800), the Tsinghua University Initiative Scientific Research Program, the Tsinghua University–Peking University Center for Life Sciences and the Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases.

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L.L. and W.X. designed the synthetic route and implemented the chemical synthesis of ASFV pol X. Z.W. and W.X. performed the biochemistry and analytical experiments, and contributed equally to this work. T.F.Z. conceived the idea and wrote the paper. T.F.Z. and L.L. designed and supervised the study.

Corresponding authors

Correspondence to Lei Liu or Ting F. Zhu.

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The authors have filed a provisional patent application related to this work.

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Wang, Z., Xu, W., Liu, L. et al. A synthetic molecular system capable of mirror-image genetic replication and transcription. Nature Chem 8, 698–704 (2016). https://doi.org/10.1038/nchem.2517

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