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On gene silencing by the X10-23 DNAzyme

Nature Chemistry volume 14, pages 855–858 (2022)Cite this article

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Matters Arising to this article was published on 18 July 2022

The Original Article was published on 25 March 2021

arising from Y. J. Wang et al. Nature Chemistry https://doi.org/10.1038/s41557-021-00645-x (2021).

The recently described in vivo gene silencing activity of a xeno nucleic acid (XNA)-modified version of the classic 10-23 DNAzyme (X10-23) has created substantial interest1,2,3. Our data suggest that the core claim of the manuscript—that the observed gene silencing activity is mediated by the RNA endonuclease catalytic activity of the X10-23 DNAzyme (rather than an antisense effect)—should be reconsidered. We have arrived at this opinion both through examination of the data in the Nature Chemistry paper (Wang et al.1), a companion paper in the Journal of the American Chemical Society (Nguyen et al.2) and by comparison with results we have obtained with the X10-23 DNAzyme (kindly provided by the authors) targeting an RNA sequence (residues 202–215) from exon 2 of the oncogene KRAS (reported as exon 1 in ref. 1). Further supporting data are provided by examination of the activities of other modified versions of the 10-23 DNAzyme, as well as all-FANA XNAzymes4, also targeting RNA sequences in KRAS exon 2.

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Fig. 1: RNase H recruitment activity of KRAS RNA-targeting X10-23 DNAzymes on long RNA substrates.

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Acknowledgements

This work was supported by the Medical Research Council (P.H., program no. MC_U105178804) and the Wellcome Trust and the Royal Society (Sir Henry Dale Fellowship to A.I.T., 215453/Z/19/Z).

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  1. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK

    Alexander I. Taylor

  2. MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK

    Philipp Holliger

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Both authors conceived and designed experiments, A.I.T. performed experiments and both authors analysed data and co-wrote the manuscript.

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Correspondence to Alexander I. Taylor or Philipp Holliger.

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Taylor, A.I., Holliger, P. On gene silencing by the X10-23 DNAzyme. Nat. Chem. 14, 855–858 (2022). https://doi.org/10.1038/s41557-022-00990-5

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