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Full-Text Articles in Medicine and Health Sciences
Cdc45 Function Alters Cell Sensitivity To Dna Topoisomerase I Poisons, Cynthia Sue Lancaster
Cdc45 Function Alters Cell Sensitivity To Dna Topoisomerase I Poisons, Cynthia Sue Lancaster
Theses and Dissertations (ETD)
Eukaryotic DNA topoisomerase I (Top1) is a highly conserved enzyme that functions to manage the torsional strain of DNA during cellular processes such as transcription, replication, chromatid condensation and recombination. The enzyme binds duplex DNA and through a series of strand cleavage and religation reactions removes positive or negative supercoils relieving torsional strain. Top1 is the sole cellular target of the anticancer agent camptothecin, which stabilizes the covalent complex. CPT cytotoxicity is S-phase dependent. It has been suggested that the mechanism of this S-phase toxicity is due to the advancing replication forks either colliding with the stabilized drug-enzyme-DNA intermediate or …
Enzyme Architecture And Flexibility Affect Dna Topoisomerase I Function, Mariè Van Der Merwe
Enzyme Architecture And Flexibility Affect Dna Topoisomerase I Function, Mariè Van Der Merwe
Theses and Dissertations (ETD)
DNA topoisomerase I (Top1) is a highly conserved enzyme composed of four domains: a positively charged N-terminus; a DNA binding/core domain that circumscribes duplex DNA; a non-conserved linker domain; and a C-terminal/catalytic domain. Top1 catalyzes changes in DNA topology by transient cleavage of a single DNA strand and the concomitant formation of a phosphotyrosyl linkage between the enzyme and the 3’ DNA end. This covalent Top1-DNA complex is the binding site for camptothecin (CPT), which selectively inhibits religation of the cleaved DNA strand. CPT binding stabilizes the covalent complex, while the collision of replication forks with CPT-Top1-DNA adducts produces DNA …