Many standard antibiotics and anti-cancer drugs block the enzymes that snip the kinks and knots out of DNA DNA tangles are lethal to cells but the drugs are increasingly encountering resistant bacteria and tumors.
A new discovery by University of California, Berkeley, biochemists could pave the way for new research into how to re-design these drugs to make them more effective poisons for cancer cells and harmful bacteria.
"The development of the anti-bacterial and anti-tumor agents that target these enzymes thus far has been done entirely in the absence of any visualization of how these drugs actually interact with the protein itself. And they have done remarkably well," said James Berger, UC Berkeley professor of molecular and cell biology. "But we have increasing problems of resistance to these drugs. Being able to see how these drugs can interact with the enzyme and DNA is going to be critical to developing the next generation of therapeutics that can be used to overcome these resistance problems."
Berger and colleagues at Emerald BioStructues of Bainbridge Island, Wash., and Vanderbilt University in Nashville, Tenn., report their new findings in a paper to be printed in the journal Nature and made available last week as an advance online publication at http://www.nature.com.
The tangles in DNA, like those in a string of holiday lights, are a result of packing some six feet of DNA into a cell nucleus so small that it is invisible to the naked eye. Every time a cell divides, it has to unpack, duplicate and repack its DNA, generating about a million tangles among the newly-copied chromosomes in the process.
As Berger has shown in previous work, enzymes called topoisomerases home in on the sharp turns in a knot and then progressively snip the DNA, unloop it, and restitch it flawlessly. If, however, the enzyme slips up, that one snip can turn into a potentially mutagenic
|Contact: Robert Sanders|
University of California - Berkeley