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Papers In Press, published online ahead of print July 30, 2002
Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799
Corresponding Author: pdarpa{at}usuhs.mil
A small fraction of topoisomerase I (TOP1) is sumoylated under basal conditions (~1%) and anticancer camptothecins that trap the TOP1-DNA covalent intermediate markedly increase the sumoylation of TOP1 (< 10%). To study the role of the sumoylation of TOP1, we mutated sites on GFP-TOP1 corresponding to the consensus sequence for protein sumoylation (
J. Biol. Chem, 10.1074/jbc.M200388200
Submitted on January 14, 2002
Revised on July 25, 2002
Accepted on July 29, 2002
Sumoylation of topoisomerase I is involved in its partitioning between nucleoli and nucleoplasm and its clearing from nucleoli in response to camptothecin
KxE, where is a hydrophobic residue) and assayed the mutants for basal and camptothecin-induced sumoylation. Only one of the eight mutants , K117R, located in the highly charged N-terminal region, showed a substantial reduction (~5 fold) in basal and camptothecin-induced sumoylation; thus K117 appears to be the major sumoylation site. A triple mutant having the KxE sequences flanking K117R additionally mutated (K 103,117,153R) showed little if any sumoylation, but was degraded like wild-type GFP-TOP1 during camptothecin treatment. However, K 103,117,153R-GFP-TOP1 was markedly concentrated within nucleoli, depleted from the remainder of nucleus, and failed to be cleared from nucleoli in response to camptothecin treatment. These data are consistent with a model wherein basal dynamic sumoylation within the N-terminal, highly charged, disordered region prevents TOP1 binding to sites in nucleoli, thus shifting the binding equilibrium toward the nucleoplasm; and CPT treatment, by increasing TOP1 sumoylation, further shifts the binding equilibrium resulting in delocalization of TOP1 from nucleoli.
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