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Wild-Type and Mutant Forms of p53 Activate Human Topoisomerase I: A Possible Mechanism for Gain of Function in Mutants¹

Department of Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263

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.

¹ Supported by a research grant from Taisho Pharmaceutical Co., Ltd., NIH Grant CA31101, and Roswell Park Cancer Institute Core Grant CA 16056.

² To whom requests for reprints should be addressed, at Department of Experimental Therapeutics, Room 403, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.

Received 3/ 2/98. Accepted 3/31/98.

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