Quinolone action against human topoisomerase IIalpha: stimulation of enzyme-mediated double-stranded DNA cleavage.

Bromberg KD, Burgin AB, Osheroff N
Biochemistry. 2003 42 (12): 3393-8

PMID: 12653542 · DOI:10.1021/bi027383t

Several important antineoplastic drugs kill cells by increasing levels of topoisomerase II-mediated DNA breaks. These compounds act by two distinct mechanisms. Agents such as etoposide inhibit the ability of topoisomerase II to ligate enzyme-linked DNA breaks. Conversely, compounds such as quinolones have little effect on ligation and are believed to stimulate the forward rate of topoisomerase II-mediated DNA cleavage. The fact that there are two scissile bonds per double-stranded DNA break implies that there are two sites for drug action in every enzyme-DNA cleavage complex. However, since agents in the latter group are believed to act by locally perturbing DNA structure, it is possible that quinolone interactions at a single scissile bond are sufficient to distort both strands of the double helix and generate an enzyme-mediated double-stranded DNA break. Therefore, an oligonucleotide system was established to further define the actions of topoisomerase II-targeted drugs that stimulate the forward rate of DNA cleavage. Results indicate that the presence of the quinolone CP-115,953 at one scissile bond increased the extent of enzyme-mediated scission at the opposite scissile bond and was sufficient to stimulate the formation of a double-stranded DNA break by human topoisomerase IIalpha. These findings stand in marked contrast to those for etoposide, which must be present at both scissile bonds to stabilize a double-stranded DNA break [Bromberg, K. D., et al. (2003) J. Biol. Chem. 278, 7406-7412]. Moreover, they underscore important mechanistic differences between drugs that enhance DNA cleavage and those that inhibit ligation.

MeSH Terms (22)

Amino Acid Substitution Anti-Infective Agents Antigens, Neoplasm Antineoplastic Agents Base Sequence Binding Sites Catalytic Domain DNA DNA-Binding Proteins DNA Damage DNA Repair DNA Topoisomerases, Type II Enzyme Activation Etoposide Fluoroquinolones Humans In Vitro Techniques Kinetics Models, Biological Oligodeoxyribonucleotides Recombinant Proteins Substrate Specificity

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