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Molecular image of genotoxin reveals how bacteria damage human DNA

The three-dimensional structure of a DNA-damaging, bacterial toxin has been visualized by scientists at Rockefeller University. The molecular image of the toxin, published in the May 27 issue of the journal Nature, shows exactly how the toxin is put together at the molecular level and damages human DNA. The structure also could help scientists to design new drugs to fight the wide variety of bacteria that use this toxin.

The toxin, called cytolethal distending toxin, or CDT, is used by bacteria that cause a range of diseases, from typhoid fever to diarrhea. And unlike any other bacterial toxin discovered to date, CDT attacks the DNA in human cells, creating lesions and breaks that cause cells to stop dividing and eventually die.

Principal investigator C. Erec Stebbins, Ph.D., who conducted the research with Rockefeller colleagues Dragana Nesic, Ph.D., and Yun Hsu, says that having a chemical model provides a visual blueprint for understanding how the toxin damages DNA.

"CDT may be a carcinogen because it damages DNA," says Stebbins, assistant professor and head of the Laboratory of Structural Microbiology at Rockefeller. "That makes CDT interesting in terms of both infectious disease and cancer."

While normal cells regularly replicate, or make exact copies of themselves, cells exposed to CDT go into "cell cycle arrest." While some CDT-invaded cells continue to grow in size without dividing, others commit suicide through a process known as apoptosis.

These cellular reactions to CDT invasion are not surprising because cells have "checkpoint" mechanisms to insure that DNA sequences are copied correctly during the process of replication, says Stebbins. When a "mistake" or a break in DNA is detected, cells either repair the DNA, or, if it is irreparable, they stop replicating and often commit suicide. This process is a protection mechanism to stop mistakes from being propagated.

Stebbins says that CDT-containing bacteria
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26-May-2004


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