Sneaking into DNA

By Eric Sauter

Scripps Research Institute Professors Dale L. Boger and Joel Gottesfeld, along with John Trzupek, a graduate student in Boger’s laboratory, have uncovered a pair of extraordinarily clever molecular break-in artists—two natural occurring anti-tumor agents that are able to alter DNA, even when it is bound up and hidden deep inside the cell. This research may help lead the way to improved cancer treatments.

While DNA in a test tube looks like thick gobs of gooey white silk, inside the nucleus of eukaryotic cells the compound is exquisitely compact. To fit into the remarkably small space of the nucleus, it is first packaged into chromatin, a compression process that dramatically shrinks what is in reality an enormous amount of DNA; estimates of the actual length of DNA crammed into the cell nucleus usually run between 2 and 3 meters. The compressed DNA is wrapped around several basic proteins called histones to form the nucleosome core particle (NCP), a process which changes its physical properties considerably. This packing also serves a regulatory function, preventing proteins and reversibly binding small molecules from gaining access to hidden parts of the DNA.

The two agents in question, duocarmycin SA and yatakemycin are two natural products derived from a species of Streptomyces, a large family of bacteria first discovered in 1943 that have yielded most of the antibiotics used today. Both duocarmycin SA and yatakemycin are extremely potent cyto-toxic compounds because of their unique ability to modify DNA through alkylation. Although both these small molecules were known to alter DNA in vivo, the exact sites being modified within the cellular DNA were unknown. Not anymore. In their new study, Boger and Gottesfeld have shown that these two natural compounds react with both free DNA and DNA within the NCP, and that the selectivity and efficiency of their DNA-alkylation abilities were relatively unaffected by NCP packaging.

Boger and Gottesfeld highlighted the fact that NCP-packaged DNA exists in a dynamic mobile state rather than a static one, and that this property plays an important role in making DNA hidden within the NCP fully accessible to this particular class of alkylating agents. These new findings may prove to be useful in further understanding the precise mechanisms of the compounds' anti-tumor activity in vivo, and may help in the future design of more potent anti-cancer compounds.

Their study, which will be published in the February issue of Nature Chemical Biology, was released in an advanced version on the publication’s website on January 15. Boger is the Richard and Alice Cramer Professor of Chemistry in Scripps Research Department of Chemistry and a member of the Skaggs Institute for Chemical Biology. Joel M. Gottesfeld is a professor in the Scripps Research Department of Molecular Biology. Their research was funded by a grant from The National Institutes of Health.

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