New way to lock DNA-slicing enzyme onto chromosomes could lead to novel anti-cancer drugs
St. Jude Children's Research Hospital (ALSAC)
Investigators at St. Jude Children's Research Hospital have discovered a new way that an enzyme crucial to the cell's ability to decode genes and duplicate chromosomes can be turned into a poison inside cancer cells.
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 other enzymes follow behind, unraveling the DNA. If the enzyme machinery following Top 1 is decoding a gene, only that part of the chromosome must be unraveled. If the machinery is duplicating the chromosome, the process of unraveling must continue along the entire molecule.
St. Jude investigators modified the top and bottom ends of the C-shaped enzyme so that the tips of the open ends of the enzyme were pulled together and locked Top 1 into place around the DNA. The Top 1 then acted as a roadblock to the enzyme machinery behind it.
"We found that Top 1 didn't even have to cut the DNA once it locked down on it in order to set off cell death," Bjornsti said. "Just being a roadblock to the enzyme machinery moving along the DNA behind it was enough to kill the cell."
This differs from the way a currently used anti-cancer drug, camptothecin (CPT), works. CPT works only during the part of the cell's life cycle called S phase, when the cell synthesizes duplicate chromosomes.
Because the new strategy can work whether the cell is in S phase or just decoding a single gene, a drug based on this approach could be particularly versatile.
"What's particularly exciting about our finding is that it is a proof-of-principle for a new class of anti-cancer drugs that can work in combination with CPT, a drug that has already shown itself to be a valuable cancer treatment," Bjornsti said. "By targeting Top 1 a different way, it might be possible to lessen the ability of cancer cells to become resistant to treatment, as they might when treated with CPT alone."
The use of CPT in pediatric cancer was also pioneered at St. Jude.
Other authors of the study include Michael Woo and Hong Guo (St. Jude), and Carmen Losasso, Luca Pattarello and Piero Benedetti (University of Padua, Italy).
This work was supported in part by the National Institutes of Health, Ministero dell'Instruzione, dell'Universitą e della Ricerca Confinanziamento, Associazione Italiana per la Ricerca Sul Cancro, and ALSAC.
For more information, or to contact St. Jude Children's Research Hospital (ALSAC), see their website at: www.stjude.org
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