Cross-Linking Topoisomerase 1 Prevents Cell Replication

Researchers studying the processes used by the cell to decode and duplicate DNA molecules have found that a chemical modification of the Topoisomerase 1 enzyme, the enzyme that unlocks and unwinds the DNA double helix, locks it into place on the DNA strand and prevents cell replication.

Investigators at St. Jude Children's Research Hospital (Memphis, TN, USA; www.stjude.org) used molecular modeling to design a disulfide bond between residues Gly-365 and Ser-534 of the Topoisomerase 1 protein, to cross-link protein loops more proximal to the active-site tyrosine than the protein loops held by the Lys-369–Glu-497 salt bridge. This cross-linking prevented DNA rotation and unwinding. These findings were published in the November 25, 2003, issue of the Proceedings of the [U.S.] National Academy of Sciences.

"We showed that modifying Topoisomerase 1 so it became locked onto the DNA molecule is enough to cause cell death,” explained senior author Dr. Mary-Ann Bjornsti, associate member, molecular pharmacology department, St. Jude Children's Research Hospital.

The authors speculated that this new understanding into the functioning of Topoisomerase 1 will spur the generation of a new class of anticancer drugs. "What is particularly exciting about our finding is that it is a proof-of-principle for a new class of anticancer drugs that can work in combination with irinitecan (CPT), a drug that has already shown itself to be a valuable cancer treatment,” said Dr. Bjornsti. "By targeting Topoisomerase 1in 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.”





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