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Molecular and Cellular Biology, November 1999, p. 7501-7510, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

An ATP/ADP-Dependent Molecular Switch Regulates the Stability of p53-DNA Complexes

Andrei L. Okorokov and Jo Milner*

YCR P53 Research Group, Department of Biology, University of York, York, YO10 5DD, United Kingdom

Received 14 May 1999/Returned for modification 9 July 1999/Accepted 27 July 1999

Interaction with DNA is essential for the tumor suppressor functions of p53. We now show, for the first time, that the interaction of p53 with DNA can be stabilized by small molecules, such as ADP and dADP. Our results also indicate an ATP/ADP molecular switch mechanism which determines the off-on states for p53-DNA binding. This ATP/ADP molecular switch requires dimer-dimer interaction of the p53 tetramer. Dissociation of p53-DNA complexes by ATP is independent of ATP hydrolysis. Low-level ATPase activity is nonetheless associated with ATP-p53 interaction and may serve to regenerate ADP-p53, thus recycling the high-affinity DNA binding form of p53. The ATP/ADP regulatory mechanism applies to two distinct types of p53 interaction with DNA, namely, sequence-specific DNA binding (via the core domain of the p53 protein) and binding to sites of DNA damage (via the C-terminal domain). Further studies indicate that ADP not only stabilizes p53-DNA complexes but also renders the complexes susceptible to dissociation by specific p53 binding proteins. We propose a model in which the DNA binding functions of p53 are regulated by an ATP/ADP molecular switch, and we suggest that this mechanism may function during the cellular response to DNA damage.

* Corresponding author. Mailing address: YCR P53 Research Group, Department of Biology, University of York, York YO10 5DD, United Kingdom. Phone: (44) 01904 432891. Fax: (44) 01904 432808. E-mail: ajm24{at}york.ac.uk.

Molecular and Cellular Biology, November 1999, p. 7501-7510, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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