Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol gamma.
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 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.
Achanta
Geetha
G
Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sasaki
Ryohei
R
Feng
Li
L
Carew
Jennifer S
JS
Lu
Weiqin
W
Pelicano
Helene
H
Keating
Michael J
MJ
Huang
Peng
P
D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D000074002:DNA Polymerase gamma; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D042822:Genomic Instability / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017931:DNA Primers; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase