P53 in mitochondria enhances the accuracy of DNA synthesis

Abstract

Mitochondrial localization of p53 was observed in stressed and unstressed cells. p53 is involved in DNA repair and apoptosis. It exerts physical and functional interactions with mitochondrial DNA and DNA polymerase gamma (pol gamma). The functional cooperation of p53 and pol gamma during DNA synthesis was examined in the mitochondrial fraction of p53-null H1299 cells, as the source of pol gamma. The results show that p53 may affect the accuracy of DNA synthesis in mitochondria: (1) the excision of a misincorporated nucleotide increases in the presence of (a) recombinant wild-type p53 (wtp53); (b) cytoplasmic fraction of LCC2 cells expressing endogenous wtp53 (but not specifically pre-depleted fraction); (c) cytoplasmic extract of H1299 cells overexpressing wtp53, but not exonuclease-deficient mutant p53-R175H. (2) Mitochondrial extracts of HCT116(p53+/+) cells display higher exonuclease activity compared with that of HCT116(p53-/-) cells. Addition of exogenous p53 complements the HCT116(p53-/-) mitochondrial extract mispair excision. Furthermore, the misincorporation was lower in the mitochondrial fraction of HCT116(p53+/+) cells as compared with that of HCT116(p53-/-) cells. (3) Irradiation-induced mitochondrial translocation of endogenous p53 in HCT116(p53+/+) cells correlates with the enhancement of error-correction activities. Taken together, the data suggest that p53 in mitochondria may be a component of an error-repair pathway and serve as guardian of the mitochondrial genome. The function of p53 in DNA repair and apoptosis is discussed.