Journal
EMBO JOURNAL
Volume 24, Issue 19, Pages 3482-3492Publisher
WILEY
DOI: 10.1038/sj.emboj.7600819
Keywords
DNA polymerase gamma; mitochondria; mutation; p53; reactive oxygen species (ROS)
Categories
Funding
- NCI NIH HHS [P30 CA016672, R01 CA100428, CA85563, CA16672, CA109041, CA100428, R01 CA085563, R01 CA109041] Funding Source: Medline
Ask authors/readers for more resources
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 gamma ( pol gamma) in response to mtDNA damage induced by exogenous and endogenous insults including ROS. The p53 protein physically interacts with mtDNA and pol gamma, and enhances the DNA replication function of pol gamma. 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 wildtype p53. This study provides a mechanistic explanation for the accelerating genetic instability and increased ROS stress in cancer cells associated with loss of p53.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available