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Toxicity and repair of DNA adducts produced by the natural product yatakemycin

Nature Chemical Biology volume 13, pages 1002–1008 (2017)Cite this article

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Abstract

Yatakemycin (YTM) is an extraordinarily toxic DNA alkylating agent with potent antimicrobial and antitumor properties and is the most recent addition to the CC-1065 and duocarmycin family of natural products. Though bulky DNA lesions the size of those produced by YTM are normally removed from the genome by the nucleotide-excision repair (NER) pathway, YTM adducts are also a substrate for the bacterial DNA glycosylases AlkD and YtkR2, unexpectedly implicating base-excision repair (BER) in their elimination. The reason for the extreme toxicity of these lesions and the molecular basis for the way they are eliminated by BER have been unclear. Here, we describe the structural and biochemical properties of YTM adducts that are responsible for their toxicity, and define the mechanism by which they are excised by AlkD. These findings delineate an alternative strategy for repair of bulky DNA damage and establish the cellular utility of this pathway relative to that of NER.

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Figure 1
Figure 2: Determination of YTM resistance.
Figure 3: Characterization of YTMA-DNA.
Figure 4: Excision of YTMA by AlkD.
Figure 5: Excision of a fluorinated YTMA analog (YTMAF) by AlkD.
Figure 6: Inhibition of AP-DNA incision.

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Acknowledgements

We thank Y. Igarashi (Toyama Prefectural University) for providing yatakemycin. This work was funded by the National Science Foundation (MCB-1517695) and the National Institutes of Health (R01 ES019625). Use of the Advanced Photon Source, an Office of Science User Facility operated for the US Department of Energy Office of Science by Argonne National Laboratory, was supported by the US Department of Energy (DE-AC02-06CH11357). Use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (085P1000817). E.A.M. was partially supported by the Vanderbilt Training Program in Environmental Toxicology (T32 ES007028).

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  1. Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA

    Elwood A Mullins, Rongxin Shi & Brandt F Eichman

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Contributions

E.A.M. and B.F.E. conceived the project; E.A.M., R.S., and B.F.E. designed experiments; E.A.M. performed biochemical, biophysical, and structural experiments; R.S. performed cellular experiments; E.A.M., R.S., and B.F.E. analyzed data; E.A.M. and B.F.E. wrote the paper.

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Correspondence to Brandt F Eichman.

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Mullins, E., Shi, R. & Eichman, B. Toxicity and repair of DNA adducts produced by the natural product yatakemycin. Nat Chem Biol 13, 1002–1008 (2017). https://doi.org/10.1038/nchembio.2439

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