Repair of topoisomerase-mediated DNA damage in bacteriophage T4.

Genetics
B A Stohr, K N Kreuzer

Abstract

Type II topoisomerase inhibitors are used to treat both tumors and bacterial infections. These inhibitors stabilize covalent DNA-topoisomerase cleavage complexes that ultimately cause lethal DNA damage. A functional recombinational repair apparatus decreases sensitivity to these drugs, suggesting that topoisomerase-mediated DNA damage is amenable to such repair. Using a bacteriophage T4 model system, we have developed a novel in vivo plasmid-based assay that allows physical analysis of the repair products from one particular topoisomerase cleavage site. We show that the antitumor agent 4'-(9-acridinylamino)methanesulphon-m-anisidide (m-AMSA) stabilizes the T4 type II topoisomerase at the strong topoisomerase cleavage site on the plasmid, thereby stimulating recombinational repair. The resulting m-AMSA-dependent repair products do not form in the absence of functional topoisomerase and appear at lower drug concentrations with a drug-hypersensitive topoisomerase mutant. The appearance of repair products requires that the plasmid contain a T4 origin of replication. Finally, genetic analyses demonstrate that repair product formation is absolutely dependent on genes 32 and 46, largely dependent on genes uvsX and uvsY, and only partl...Continue Reading

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Citations

Apr 7, 2005·Chembiochem : a European Journal of Chemical Biology·Michael JahnzPetra Schwille
Apr 22, 2003·Proceedings of the National Academy of Sciences of the United States of America·George Hong, Kenneth N Kreuzer
Jun 30, 2001·Molecular Cell·T UsuiJ H Petrini
Jul 19, 2001·Proceedings of the National Academy of Sciences of the United States of America·J W GeorgeK N Kreuzer
Jul 22, 2006·Experimental Cell Research·Takehiko UsuiMonica Morales
Nov 28, 2002·Genetics·Bradley A Stohr, Kenneth N Kreuzer
Feb 18, 2004·Molecular Cell·John C Connelly, David R F Leach
Nov 13, 2008·Molecular and Cellular Biology·Carrie A AdelmanJohn H J Petrini
Mar 11, 2003·Microbiology and Molecular Biology Reviews : MMBR·Eric S MillerWolfgang Rüger
Sep 5, 2002·Genes & Development·Carla F BenderJohn H J Petrini

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