Related Experiment Video

Updated: Oct 17, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

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

Published on: August 4, 2019

Mechanism of rescue of common p53 cancer mutations by second-site suppressor mutations

P V Nikolova1, K B Wong, B DeDecker

  • 1Cambridge University Chemical Laboratory and Cambridge Centre for Protein Engineering, MRC Centre, Hills Road, Cambridge CB2 2QH, UK.

The EMBO Journal
|February 2, 2000
PubMed

Insights

Second-site mutations can restore tumor suppressor p53 (mutant) function. Some suppressors globally stabilize p53 mutants, while others specifically alter mutant structures to restore DNA binding and gene regulation.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • The p53 tumor suppressor protein is frequently inactivated by mutations in its core domain, leading to loss of function.
  • Understanding the mechanisms of suppressor mutations is crucial for developing therapeutic strategies targeting p53 mutants.

Purpose of the Study:

  • To investigate the mechanisms by which second-site suppressor mutations restore the function of cancer-associated p53 mutants.
  • To differentiate between global stability suppressors and mutation-specific suppressors of p53.

Main Methods:

  • Analysis of protein stability and DNA-binding activity of wild-type and mutant p53.
  • Double-mutant cycle analysis to determine the energetic contributions of suppressor mutations.
  • Nuclear Magnetic Resonance (NMR) spectroscopy to compare the structures of wild-type, mutant, and suppressed p53 variants.

Main Results:

  • N239Y and N268D mutations act as global stabilizers, increasing the stability of p53 mutants G245S and V143A.
  • H168R mutation specifically suppresses the R249S mutation by restoring DNA binding affinity without significantly altering R249S stability.
  • NMR data revealed that H168R reverts structural changes induced by the R249S mutation.

Conclusions:

  • Suppressor mutations can restore p53 function through distinct mechanisms: global stabilization or specific structural reversion.
  • Restoring function of mutants like V143A and G245S may be achievable with small molecules that stabilize the native structure.
  • Mutants like R249S may require therapeutic strategies that alter the mutant's specific structure.

More Related Videos

Detection of Aggregation-Prone Behavior in Mutant P53 V157F Breast Cancer Cells Using Multipoint Thioflavin T Fluorescence04:56

Detection of Aggregation-Prone Behavior in Mutant P53 V157F Breast Cancer Cells Using Multipoint Thioflavin T Fluorescence

Published on: December 30, 2025

A Deep-sequencing-assisted, Spontaneous Suppressor Screen in the Fission Yeast Schizosaccharomyces pombe07:55

A Deep-sequencing-assisted, Spontaneous Suppressor Screen in the Fission Yeast Schizosaccharomyces pombe

Published on: March 7, 2019

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...