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J. Biol. Chem., Vol. 277, Issue 42, 40020-40026, October 18, 2002
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From the Previous studies identified a small fraction of
putatively sumoylated topoisomerase I (TOP1) under basal conditions
(~1%), and anticancer camptothecins that trap the TOP1-DNA covalent
intermediate markedly increase the sumoylation of TOP1 ( Department of Biochemistry and Molecular
Biology, Uniformed Services University of the Health Sciences,
Bethesda, Maryland 20814-4799 and the § Division of
Molecular Pharmacology, Department of Molecular Genetics, and
Department of Pharmaceutics and Pharmacodynamics, University of
Illinois, Chicago, Illinois 60607
10%). To
study the role of the sumoylation of TOP1, we mutated sites on green
fluorescent protein (GFP)-TOP1 corresponding to the consensus sequence
for protein sumoylation (
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 NH2-terminal region, showed a
substantial reduction (~5-fold) in basal and camptothecin-induced
sumoylation; thus, Lys-117 appears to be the major sumoylation site. A
triple mutant having the KXE sequences flanking K117R
additionally mutated (K103R/K117R/K153R) showed little if any
sumoylation, but was degraded like wild-type GFP-TOP1 during
camptothecin treatment. However, K103R/K117R/K153R-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 transient sumoylation of the NH2-terminal, highly charged, disordered region prevents TOP1 binding to sites in nucleoli, thus driving it to bind in the nucleoplasm; and camptothecin treatment, which increases TOP1 sumoylation, further shifts the binding resulting in delocalization of TOP1 from nucleoli to nucleoplasm.
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