Yeast Gene for a Tyr-DNA Phosphodiesterase that Repairs Topoisomerase I Complexes

TLDR

Covalent intermediates between topoisomerase I and DNA can become dead‑end complexes that lead to cell death. The study isolates the gene encoding an enzyme that hydrolyzes the covalent bond between topoisomerase I and DNA. The gene encodes a Tyr‑DNA phosphodiesterase that cleaves the protein–DNA linkage, enabling repair. Yeast mutants lacking this enzyme are hypersensitive to agents that increase covalent complexes, the gene is conserved across eukaryotes, and its presence in humans may affect the efficacy of topoisomerase I poisons such as camptothecins.

Abstract

Covalent intermediates between topoisomerase I and DNA can become dead-end complexes that lead to cell death. Here, the isolation of the gene for an enzyme that can hydrolyze the bond between this protein and DNA is described. Enzyme-defective mutants of yeast are hypersensitive to treatments that increase the amount of covalent complexes, indicative of enzyme involvement in repair. The gene is conserved in eukaryotes and identifies a family of enzymes that has not been previously recognized. The presence of this gene in humans may have implications for the effectiveness of topoisomerase I poisons, such as the camptothecins, in chemotherapy.