Two anti-tumor agents are able to modify DNA, even when it is all bound up inside cells, according to a paper in the February 2006 issue of Nature Chemical Biology. Unlike 'free' DNA in a test tube that is all stretched out, DNA inside cells is tightly coiled around proteins called histones to form the nucleosome core particle (NCP). This packing allows lots of DNA to fit into the small space of the nucleus, but also has a function in regulating access to DNA. In the case of some small molecules, this packing prevents access to buried parts of the DNA.
Duocarmycin SA and yatakemycin are two natural products that have potent anti-tumor activity because of their ability to modify DNA. Although these small molecules were known to function in vivo, it was not clear which sites within the cellular DNA were being modified. Dale Boger and colleagues have now shown that these natural products react with free DNA and DNA in NCPs with the same speed and sequence preferences. This result emphasizes how the mobility of packaged DNA can allow small molecules to sneak into tightly packed locations.
This information will prove critical for understanding the precise mechanisms of the compounds' anti-tumor activity in vivo, and may prove useful for designing more potent anti-cancer compounds.
Dale Boger (The Scripps Research Institute, La Jolla, CA, USA)
Abstract available online.
(C) Nature Chemical Biology press release.
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