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Vol. 56, Issue 6, 1105-1115, December 1999
Istituto di Biologia Cellulare, "Campus Adriano
Buzzati-Traverso" Consiglio Nazionale delle Ricerche, Rome, Italy
(P.F., J.F.A., A.S., R.H.B., P.B.); and Department of Pharmaceutical
Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
(M.-A.B.)
DNA topoisomerase I (Top1p) relaxes supercoiled DNA by the
formation of a covalent intermediate in which the active site tyrosine is transiently bound to the severed DNA strand. The antineoplastic agent camptothecin (Cpt) specifically targets Top1p and several mutations have been isolated that render the enzyme Cpt resistant. The
mutated residues, although located in different regions of the enzyme,
may constitute part of the Cpt binding site. To begin identifying the
structural features of DNA Top1p important for Cpt-induced
cytotoxicity, we developed a novel yeast genetic screen to isolate
catalytically active, yet Cpt-resistant enzymes from a pool of human
top1 mutants. Among the mutations isolated were substitutions of Ser or Val for Gly363, which like the Gly363 to Cys
mutation previously reported by us, suppressed the Cpt sensitivity of
Top1p. In contrast, each amino-acid substitution differed in its
ability to suppress the lethal phenotype and catalytic activity of a
human top1 mutant top1T718A that resembles Cpt by stabilizing the covalent intermediate. Biochemical analyses and molecular modeling support a model where interactions between two
conserved domains, a central "lip" region containing residue Gly363
and the residues around the active site tyrosine (Tyr723), directly
affect the formation of the Cpt-binding site and enzyme catalysis.
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