Human REV3 DNA Polymerase Zeta Localizes to Mitochondria and Protects the Mitochondrial Genome

• Published in: PloS one 2015-10, Vol.10 (10), p.e0140409
• Main Authors: Singh, Bhupendra, Li, Xiurong, Owens, Kjerstin M, Vanniarajan, Ayyasamy, Liang, Ping, Singh, Keshav K
• Format: Article
• Language: English
• Subjects: Aging; Amino Acid Sequence; Analysis; Animals; Biotechnology; Breast cancer; Breast Neoplasms - pathology; Cancer; Carcinogenesis - pathology; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Cell survival; Cytoprotection; Deactivation; Deoxyribonucleic acid; DNA; DNA Damage; DNA polymerase; DNA Polymerase gamma; DNA polymerases; DNA repair; DNA, Mitochondrial - genetics; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; DNA-directed DNA polymerase; DNA-Directed DNA Polymerase - chemistry; DNA-Directed DNA Polymerase - metabolism; Female; Fibroblasts; Genetics; Genome, Mitochondrial; Genomes; HEK293 Cells; HeLa Cells; Humans; Inactivation; Invasiveness; Localization; Mammalian cells; Mammals; Membrane potential; Mice; Mitochondria; Mitochondria - enzymology; Mitochondrial DNA; Molecular Sequence Data; Mutagenesis; Mutation; NIH 3T3 Cells; Oxidative Phosphorylation; Protein Binding; Protein Transport; Proteins; Saccharomyces cerevisiae; Tumor cell lines; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0140409

To date, mitochondrial DNA polymerase γ (POLG) is the only polymerase known to be present in mammalian mitochondria. A dogma in the mitochondria field is that there is no other polymerase present in the mitochondria of mammalian cells. Here we demonstrate localization of REV3 DNA polymerase in the mammalian mitochondria. We demonstrate localization of REV3 in the mitochondria of mammalian tissue as well as cell lines. REV3 associates with POLG and mitochondrial DNA and protects the mitochondrial genome from DNA damage. Inactivation of Rev3 leads to reduced mitochondrial membrane potential, reduced OXPHOS activity, and increased glucose consumption. Conversely, inhibition of the OXPHOS increases expression of Rev3. Rev3 expression is increased in human primary breast tumors and breast cancer cell lines. Inactivation of Rev3 decreases cell migration and invasion, and localization of Rev3 in mitochondria increases survival and the invasive potential of cancer cells. Taken together, we demonstrate that REV3 functions in mammalian mitochondria and that mitochondrial REV3 is associated with the tumorigenic potential of cells.