Cross-Linking Topoisomerase 1 Prevents Cell Replication

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.”





Related Links:
St. Jude Children's Research Hospital