Wild-type and mutant forms of p53 activate human topoisomerase I: a possible mechanism for gain of function in mutants.
p53-interacting proteins from mouse epidermal cells and human myelogenous leukemia cells were isolated by affinity chromatography using glutathione S-transferase (GST)-p53 fusion proteins. One of these proteins was topoisomerase I, whose interaction with p53 was recently reported. A carboxyl-terminal fragment containing the last 92 amino acids of p53 (GST-299-390) was sufficient for binding to topoisomerase I. Nanomolar concentrations of either GST-p53 or GST-299-390 enhanced the catalytic activity of purified human topoisomerase I. Purified wild-type human p53 and point mutants Ser-239, Ser-245, and His-273 were equivalent in their enhancement of human topoisomerase I activity. Because topoisomerase I is thought to promote genetic recombination, competence to enhance topoisomerase I catalytic activity coupled with a deficiency in transcriptional activity may be a mechanism for gain of function in mutant p53 proteins.
Albor
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Department of Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Kaku
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Kulesz-Martin
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D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D004264:DNA Topoisomerases, Type I