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Site selectivity of platinum anticancer therapeutics

Nature Chemical Biology volume 4, pages 110–112 (2008)Cite this article

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Abstract

X-ray crystallographic and biochemical investigation of the reaction of cisplatin and oxaliplatin with nucleosome core particle and naked DNA reveals that histone octamer association can modulate DNA platination. Adduct formation also occurs at specific histone methionine residues, which could serve as a nuclear platinum reservoir influencing adduct transfer to DNA. Our findings suggest that the nucleosome center may provide a favorable target for the design of improved platinum anticancer drugs.

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Figure 1: X-ray crystallographic analysis revealing DNA and histone platinum adduct positions in the NCP.
Figure 2: Exonuclease footprinting analysis revealing drug-specific differences in platination site selectivity between naked and nucleosomal DNA.

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Acknowledgements

C.A.D. dedicates this work to the memory of Lois Joan Varallo. Thanks to D. Vasudevan, K.A. Mohideen, C. Schulze-Briese and staff at the X06SA beam line of the Swiss Light Source for assistance with data collection. C.A.D. is very grateful to G.E. Davey for input on the manuscript and unreserved support. This work was supported by a Nanyang Technological University grant and an Academic Research Council grant from the Ministry of Education, Singapore.

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Authors and Affiliations

  1. Division of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore

    Bin Wu & Curt A Davey

  2. Division of Genomics and Genetics, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore

    Peter Dröge

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  1. Bin Wu
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  2. Peter Dröge
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  3. Curt A Davey
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Contributions

B.W. planned and performed experiments; P.D. provided expertise for footprinting analysis and input on the manuscript; C.A.D. designed research, conducted analysis and wrote the manuscript.

Corresponding author

Correspondence to Curt A Davey.

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Supplementary Figures 1–3, Supplementary Tables 1–3 and Supplementary Methods (PDF 677 kb)

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Wu, B., Dröge, P. & Davey, C. Site selectivity of platinum anticancer therapeutics. Nat Chem Biol 4, 110–112 (2008). https://doi.org/10.1038/nchembio.2007.58

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