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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

Excision of nucleoside analogs in mitochondria by p53 protein

Mary Bakhanashvili1, Shai Grinberg, Elad Bonda

  • 1Infectious Diseases Unit, Sheba Medical Center, Tel-Hashomer 52621, Israel. bakhanus@yahoo.com

AIDS (London, England)
|March 17, 2009
PubMed
Abstract

Insights

The tumor suppressor protein p53 can excise nucleoside analogs from mitochondrial DNA, preventing mitochondrial diseases. This proofreading function aids DNA polymerase gamma during replication, reducing harmful mutations.

Area of Science:

  • Mitochondrial biology
  • Molecular genetics
  • Cancer research

Background:

  • Nucleoside analogs used in HIV treatment can be incorporated into mitochondrial DNA by DNA polymerase gamma.
  • This incorporation can lead to mitochondrial DNA depletion and mutations, potentially causing mitochondrial diseases.
  • The tumor suppressor protein p53 possesses 3' --> 5' exonuclease activity, suggesting a proofreading role.

Purpose of the Study:

  • To investigate the capacity of p53 to remove nucleoside analogs from DNA within mitochondria.
  • To explore the functional interaction between p53 and DNA polymerase gamma in mitochondrial DNA replication.

Main Methods:

  • Utilized mitochondrial fractions from p53-null H1299 cells to study DNA polymerase gamma activity.
  • Employed primer extension assays to analyze the incorporation and excision of nucleoside analogs.
  • Compared p53's effect using purified recombinant p53, cellular extracts, and p53-deficient/proficient cell lines (HCT116).

Main Results:

  • Purified p53 and wild-type p53-expressing extracts enhanced the excision of nucleoside analogs from mitochondrial DNA.
  • Exonuclease-deficient p53 mutants did not show this effect.
  • HCT116 cells with functional p53 incorporated fewer nucleoside analogs and incorrect nucleotides into mitochondrial DNA compared to p53-null cells.
  • Irradiation-induced p53 elevation in mitochondria correlated with reduced analog incorporation.

Conclusions:

  • Mitochondrial p53 likely interacts with DNA polymerase gamma, providing a proofreading mechanism.
  • This interaction facilitates the excision of nucleoside analogs and corrects polymerization errors during mitochondrial DNA replication.
  • p53's mitochondrial role may be crucial in preventing drug-induced mitochondrial toxicity and disease.

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