CHEVY CHASE, Md.—Researchers at Howard Hughes Medical Institute (HHMI), the Institute of Biotechnology in Vilnius, Lithuania, and the Institute of Organic Chemistry in Aachen, Germany, have developed a new technique using DNA methyltransferases that will allow them to modify specific sequences within a DNA molecule. The approach, which helps reveal the impact of biochemical alterations to DNA, could have far-reaching implications for DNA-based medical diagnosis and nanobiotechnology, according to HHMI, and may become a therapeutic modality in and of itself, as well.
Methyltransferases require a source for the methyl groups that they attach to DNA, and most often that source is a molecule called S-Adenosyl-L-methionine (AdoMet), sometimes known as SAM or SAMe. Methyltransferases grab the methyl group from AdoMet and transfer it directly to DNA, positioning it with enviable specificity within the sequence. This specificity suggests that the enzymes can be a useful tool in the laboratory. But Dr. Saulius Klimasauskas--an HHMI international research scholar at the Institute of Biotechnology --and his colleagues wanted the flexibility to attach more than just a simple methyl group. To demonstrate the technique's potential to alter DNA function, the researchers modified DNA in a position that blocked another enzyme's ability to snip the molecule at its target site.
"No one has really thought about possible applications [of this] before because no one thought it was possible," says Klimasauskas, predicting that "DNA methyltransferases will become a standard laboratory tool like restriction endonucleases."
Due to their sequence-specific nature, Klimasauskas and his colleagues have indicated that methyltransferases have a distinct advantage over other commonly used labeling techniques for DNA and other biopolymers. "Our approach allows labeling of large native DNA molecules at specific internal or terminal loci," Klimasauskas explains.
Their work was published in an early online publication on Nov. 27, 2005, in Nature Chemical Biology, and Klimasauskas says the most obvious applications for the technology are diagnostics and nanotechnology. Applications for drug discovery exist as well, he notes, though they may be less direct and longer-term.
"This technology may become a new type of therapy itself, as it allows targeted deposition of extended groups of biopolymers, which might lead to the disruption or crosslinking of certain key intermolecular interactions," Klimasauskas speculates. "We expect that this might eventually also work in vivo, but many technical problems need to be solved. Yet another direction could be functional proteomics—the identification of unknown natural methylation targets or new methyltransferases in the cell."