Inhibition of Flp recombinase by the topoisomerase I-targeting drugs, camptothecin and NSC-314622.
Recombinases of the lambda-Int family and type IB topoisomerases act by introducing transient single strand breaks in DNA using chemically identical reaction schemes. Recent structural data have supported the relationship between the two enzyme groups by revealing considerable similarities in the architecture of their catalytic pockets. In this study we show that the Int-type recombinase Flp is inhibited by the two structurally unrelated topoisomerase I-directed anti-cancer drugs, camptothecin (CPT) and NSC-314622. The interaction of these drugs with topoisomerase I is very specific with several single amino acid substitutions conferring drug resistance to the enzyme. Thus, the observed interaction of CPT and NSC-314622 with Flp, which is comparable to their interaction with the cleavage complex formed by topoisomerase I, strongly supports a close mechanistic and evolutionary relationship between the two enzymes. The results suggest that Flp and other Int family recombinases may provide model systems for dissecting the molecular mechanisms of topoisomerase I-directed anti-cancer therapeutic agents.
Frøhlich
R F
RF
Department of Molecular and Structural Biology, University of Aarhus, Building 130, C. F. Møllers Allé, DK-8000 Aarhus C, Denmark.
Hansen
S G
SG
Lisby
M
M
Grainge
I
I
Westergaard
O
O
Jayaram
M
M
Knudsen
B R
BR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002166:Camptothecin / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004254:DNA Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019143:Evolution, Molecular; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007192:Indenes; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004254:DNA Nucleotidyltransferases; C045119:FLP recombinase; C113496:NSC 314622; D002166:Camptothecin