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Sequence-specific Interaction of a Conformational Domain of p53 with DNA¹

Departments of Thoracic and Cardiovascular Surgery [R. S., J. A. R., S. A. M.] and Tumor Biology [J. A. R.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Mutations within a conserved "conformational" domain of the p53 protein have frequently been observed in a wide variety of human cancers. A hybrid protein containing the wild-type conformational domain of p53 fused to protein A bound to calf thymus DNA and a specific p53 DNA-binding motif. Hybrid proteins containing mutations in p53 bound to DNA less efficiently than wild-type hybrid protein. In addition, competition experiments showed that mutated p53 DNA-binding motif failed to interact with p53 hybrid proteins. The DNA-binding activity of wild-type p53 hybrid protein was inhibited by the metal chelator 1,10-phenanthroline. These results demonstrate that DNA-binding activity resides in the conformational domain of p53, providing a structural model for disruption of DNA binding by mutation. Furthermore, metal ions may regulate binding of p53 to DNA by modulating its conformation.

¹ This work was supported by an Advanced Research Proposal Grant from the Texas Higher Education Coordinating Board (015-033) (S. A. M.); by grants RO1 CA45187 from the National Cancer Institute, NIH; a grant from the Mathers Foundation (J. A. R.); by gifts to the Division of Surgery from Tenneco and Exxon for the Core Lab Facility; by The University of Texas M. D. Anderson Cancer Center Core Grant (NCI CA16672) and the Automated DNA Sequencing Core Facility (NCI 2P30-CA 16672-018).

² To whom requests for reprints should be addressed.

Received 6/18/93. Accepted 10/ 5/93.

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