Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol γ

Geetha Achanta, Ryohei Sasaki, Li Feng, Jennifer S. Carew, Weiqin Lu, Helene Pelicano, Michael J. Keating, Peng Huang

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

Mitochondrial DNA (mtDNA) mutations and deletions are frequently observed in cancer, and contribute to altered energy metabolism, increased reactive oxygen species (ROS), and attenuated apoptotic response to anticancer agents. The mechanisms by which cells maintain mitochondrial genomic integrity and the reason why cancer cells exhibit more frequent mtDNA mutations remain unclear. Here, we report that the tumor suppressor molecule p53 has a novel role in maintaining mitochondrial genetic stability through its ability to translocate to mitochondria and interact with mtDNA polymerase γ (pol γ) in response to mtDNA damage induced by exogenous and endogenous insults including ROS. The p53 protein physically interacts with mtDNA and pol γ, and enhances the DNA replication function of pol γ. Loss of p53 results in a significant increase in mtDNA vulnerability to damage, leading to increased frequency of in vivo mtDNA mutations, which are reversed by stable transfection of wild-type p53. This study provides a mechanistic explanation for the accelerating genetic instability and increased ROS stress in cancer cells associated with loss of p53.

Original languageEnglish (US)
Pages (from-to)3482-3492
Number of pages11
JournalEMBO Journal
Volume24
Issue number19
DOIs
StatePublished - Oct 5 2005
Externally publishedYes

Keywords

  • DNA polymerase γ
  • Mitochondria
  • Mutation
  • Reactive oxygen species (ROS)
  • p53

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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