The p53 tumor suppressor is a transcription factor that contains a single zinc ion near its DNA binding interface. Zn(2+) is required for site-specific DNA binding and proper transcriptional activation. In addition to its functional significance, zinc plays a dominant role in determining whether p53 folds productively or misfolds. Insufficient zinc and excess zinc cause p53 to misfold by distinct mechanisms which both result in functional loss. The zinc-binding status of p53 in the cell is impacted significantly by the presence of tumorigenic mutations and by metal ion homeostasis. This review discusses mechanisms by which zinc modulates folding and misfolding of p53, how improper metal binding and release leads to loss of function and cancer, and how misfolding can be rescued by metallochaperones.
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