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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Structural studies of p53 inactivation by DNA-contact mutations and its rescue by suppressor mutations via

Amir Eldar1, Haim Rozenberg, Yael Diskin-Posner

  • 1Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel and Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089, USA.

Nucleic Acids Research
|July 19, 2013
PubMed

Insights

Cancer-related p53 mutations can be reactivated by suppressor mutations. Structural analysis reveals rescued p53 complexes exhibit altered DNA interactions, highlighting the critical role of R273 in p53-DNA binding.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • Hot-spot mutations in p53, specifically R273H/C, are frequent in human cancers, leading to loss of tumor suppressor function.
  • Second-site suppressor mutations can restore the tumor suppressive activity of these p53 mutants.

Purpose of the Study:

  • To elucidate the structural mechanisms underlying p53 mutant reactivation by suppressor mutations.
  • To analyze the structural basis of p53-DNA interactions in wild-type, mutant, and reactivated p53 complexes.

Main Methods:

  • High-resolution crystal structure determination of p53 core domains (wild-type, mutants, reactivated forms) complexed with DNA.
  • Detailed structural and computational analysis of protein-DNA interfaces and DNA helical structures.

Main Results:

  • p53 inactivation stems from the inability of mutated R273 to form stabilizing DNA backbone interactions.
  • Reactivation involves alternative interactions mediated by suppressor mutations, but the p53-DNA complex is not fully restored.
  • Reactivated complexes show Watson-Crick base pairs instead of Hoogsteen base pairs, altering DNA minor groove interactions with p53.

Conclusions:

  • The R273 residue is crucial for maintaining the specific DNA geometry and sequence recognition of wild-type p53.
  • Suppressor mutations restore p53 function through altered DNA binding modes, but not a complete reversion to the wild-type interaction.
  • Structural insights into p53 reactivation offer potential avenues for therapeutic strategies targeting cancer-associated p53 mutations.

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