The discovery is an important step toward designing a new class of anti-cancer drugs. Such drugs might be given with an existing agent that also targets this enzyme, creating a one-two punch against both solid tumors and leukemia, according to the researchers.

The enzyme, called Topoisomerase 1 (Top 1), is crucial to the cell's ability to unwind the DNA of chromosomes and separate the two strands making up a giant molecule. This activity permits the cell to transcribe (decode) specific genes or to make a copy of the entire chromosome. Duplication of chromosomes is critical to the process called mitosis, or cell division. After the cell divides, each daughter cell receives a copy of the entire set of duplicated chromosomes.

"We showed that modifying Top 1 so it became locked onto the DNA molecule is enough to cause cell death," said Mary-Ann Bjornsti, Ph.D., associate member of the St. Jude Molecular Pharmacology department. Bjornsti is the senior author of a report on this work, published in the November 25 issue of Proceedings of the National Academy of Sciences.

In order to begin unraveling the double-stranded DNA molecule, Top 1 first clamps onto the spiraled DNA molecule like a pair of C-shaped pliers grasping a twisted cable. Top 1 then breaks a chemical bond between two adjacent building blocks of one DNA strand and uses that bond to bind itself to one of the cut ends of that strand. This process allows the DNA next to Top 1 to rotate and reduce some of the tension in that part of the twisted molecule. This in turn paves the way for other enzymes to unravel the DNA and either decode a specific gene or duplicate the entire chromosome. Normally, Top 1 moves along the DNA, clipping the strand as it goes, while the o
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Contact: Bonnie Cameron
bonnie.cameron@stjude.org
901-495-4815
St. Jude Children's Research Hospital
12-Dec-2003