An ATP/ADP-dependent molecular switch regulates the stability of p53-DNA complexes

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 i ndicate an ATP/ADP molecular switch mechanism which determines the off-on s tates for p53-DNA binding. This ATP/ADP molecular switch requires dimer-dim er interaction of the p53 tetramer. Dissociation of p53-DNA complexes by AT P is independent of ATP hydrolysis. Low-level ATPase activity is nonetheles s 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 regul atory mechanism applies to two distinct types of p53 interaction with DNA, namely, sequence-specific DNA binding (via the core domain of the p53 prote in) 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 r enders the complexes susceptible to dissociation by specific p53 binding pr oteins. We propose a model in which the DNA binding functions of p53 are re gulated by an ATP/ADP molecular switch, and we suggest that this mechanism may function during the cellular response to DNA damage.