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Alkylation of duplex DNA in nucleosome core particles by duocarmycin SA and yatakemycin

Nature Chemical Biology volume 2, pages 7982 (2006) | Download Citation

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Abstract

(+)-Yatakemycin (1, Fig. 1) and (+)-duocarmycin SA (2) are exceptionally potent, naturally occurring antitumor agents that derive their biological properties through a characteristic sequence-selective DNA-alkylation reaction1,2,3,4,5. Studies have shown that both the AT-rich binding selectivity (shape-selective recognition) and the alkylation catalysis (shape-dependent catalysis) that contribute to the alkylation selectivity are dependent on the DNA minor groove shape and size characteristics of an AT-rich sequence (ref. 6 and references therein; refs. 7,8). Here we report the alkylation properties of yatakemycin and duocarmycin SA on free DNA (α-satellite DNA) and the same sequence bound in a nucleosome core particle (NCP) modeling the state of DNA in eukaryotic cells. Both compounds showed a clear, relatively unaltered ability to alkylate DNA packaged in NCPs in terms of both alkylating efficiency and sequence selectivity, despite the steric and conformational perturbations imposed by NCP packaging. These findings highlight the dynamic nature of NCP-bound DNA and illustrate that cell- and protein-free DNA-alkylation studies of members of this class of antitumor drugs provide valuable insights into their properties.

  • Compound

    (+)-yatakemycin

  • Compound

    ent-(-)-yatakemycin

  • Compound

    (+)-duocarmycin SA

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Acknowledgements

We gratefully acknowledge the financial support of the US National Institutes of Health (D.L.B., CA 41986 and CA 42056) and the Skaggs Institute for Chemical Biology. We wish to thank K. Luger (Colorado State University) for the generous gift of materials used in this work, the American Society for Engineering Education (NDSEG) for a predoctoral fellowship (J.D.T.) and R. Burnett for help with the artwork. J.D.T. is a Skaggs fellow.

Author information

Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

    • John D Trzupek
    •  & Dale L Boger
  2. Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

    • Joel M Gottesfeld
  3. Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

    • Dale L Boger

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dale L Boger.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Nucleosome reconstitution and demonstration of retention of NCP complex following DNA alkylation.

  2. 2.

    Supplementary Fig. 2

    Thermally-induced strand cleavage of a-satellite DNA and NCPs (146 bp).

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DOI

https://doi.org/10.1038/nchembio761

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