One-Dimensional Sliding of p53 Along DNA Is Accelerated in the Presence of Ca2 + or Mg2 + at Millimolar Concentrations

• Does loss of homeostatic control regulate the functional dynamics of p53?
• The sliding dynamics of p53 on DNA was measured at a single-molecule level.
• The sliding of p53 on DNA significantly depended on [Mg2 +] or [Ca2 +].
• Two sliding modes of p53 with different diffusion coefficients were observed.
• The search distance of p53 along DNA is maintained as with [Mg2 +] or [Ca2 +].

One-dimensional (1D) sliding of the tumor suppressor p53 along DNA is an essential dynamics required for its efficient search for the binding sites in the genome. To address how the search process of p53 is affected by the changes in the concentration of Mg2 + and Ca2 + after the cell damages, we investigated its sliding dynamics at different concentrations of the divalent cations. The 1D sliding trajectories of p53 along the stretched DNA were measured by using single-molecule fluorescence microscopy. The averaged diffusion coefficient calculated from the mean square displacement of p53 on DNA increased significantly at the higher concentration of Mg2 + or Ca2 +, indicating that the divalent cations accelerate the sliding likely by weakening the DNA–p53 interaction. In addition, two distributions were identified in the displacement of the observed trajectories of p53, demonstrating the presence of the fast and slow sliding modes having large and small diffusion coefficients, respectively. A coreless mutant of p53, in which the core domain was deleted, showed only a single mode whose diffusion coefficient is about twice that of the fast mode for the full-length p53. Thus, the two modes are likely the result of the tight and loose interactions between the core domain of p53 and DNA. These results demonstrated clearly that the 1D sliding dynamics of p53 is strongly dependent on the concentration of Mg2 + and Ca2 +, which maintains the search distance of p53 along DNA in cells that lost homeostatic control of the divalent cations.

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