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Volume 272, Number 19, Issue of May 9, 1997 pp. 12801-12808
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Alterations in the Catalytic Activity of Yeast DNA Topoisomerase I Result in Cell Cycle Arrest and Cell Death

(Received for publication, January 16, 1997)

Maureen D. Megonigal , Jolanta Fertala and Mary-Ann Bjornsti

From the Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Eukaryotic DNA topoisomerase I catalyzes the relaxation of supercoiled DNA through a concerted mechanism of DNA strand breakage and religation. The cytotoxic activity of camptothecin results from the reversible stabilization of a covalent enzyme-DNA intermediate. Mutations in two conserved regions of yeast DNA topoisomerase I induced a similar mechanism of cell killing, albeit through different effects on enzyme catalysis. In Top1T722Ap, substituting Ala for Thr722 reduced enzyme specific activity by 3-fold, yet enhanced the stability of the covalent enzyme-DNA complex. In contrast, Top1R517Gp was 1,000-fold less active and camptothecin resistant. Nevertheless, salt-stable DNA-enzyme intermediates were detected. Mutation of the active-site tyrosine abrogated mutant enzyme activity and cytotoxicity, while sublethal levels of top1T722A expression increased rDNA recombination. In checkpoint proficient cells, pGAL1-induced top1 expression coincided with the accumulation of a terminal G2-arrested phenotype. Although the acquisition of this phenotype did not require Rad9p, Top1R517Gp- and Top1T722Ap-induced lethality was enhanced in rad9Delta strains. Thus, despite mechanistic differences between Top1R517Gp and Top1T722Ap, the DNA lesions resulting from the enhanced stability of the covalent enzyme-DNA intermediates were sufficient to cause cell cycle arrest and cell death.


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