p53 and Zinc: A Malleable Relationship

Jeung Hoi Ha, Orjola Prela, Darren R. Carpizo, Stewart N. Loh

Research output: Contribution to journalReview articlepeer-review

Abstract

A large percentage of transcription factors require zinc to bind DNA. In this review, we discuss what makes p53 unique among zinc-dependent transcription factors. The conformation of p53 is unusually malleable: p53 binds zinc extremely tightly when folded, but is intrinsically unstable in the absence of zinc at 37°C. Whether the wild-type protein folds in the cell is largely determined by the concentration of available zinc. Consequently, zinc dysregulation in the cell as well as a large percentage of tumorigenic p53 mutations can cause p53 to lose zinc, misfold, and forfeit its tumor suppressing activity. We highlight p53’s noteworthy biophysical properties that give rise to its malleability and how proper zinc binding can be restored by synthetic metallochaperones to reactivate mutant p53. The activity and mechanism of metallochaperones are compared to those of other mutant p53-targeted drugs with an emphasis on those that have reached the clinical trial stage.

Original languageEnglish (US)
Article number895887
JournalFrontiers in Molecular Biosciences
Volume9
DOIs
StatePublished - Apr 13 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Molecular Biology

Keywords

  • cancer
  • p53 mutant rescue
  • p53 mutants
  • p53 targeted drugs
  • zinc finger transcription factor
  • zinc homeostasis
  • zinc metallochaperones

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