p53 in the mitochondria, as a trans-acting protein, provides error-correction activities during the incorporation of noncanonical dUTP into DNA

Elad Bonda, Galia Rahav, Angelina Kaya, Mary Bakhanashvili

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in mitochondrial DNA is an outcome of errors produced by DNA polymerase γ during replication and failure of the repair mechanism. Misincorporation of non-canonical dUTP leads to mutagenesis or apoptosis, and may contribute to the cytotoxic effects of 5'-fluorouracil chemotherapy. Tumor suppressor p53 protein in the mitochondria displays physical and functional interactions with mitochondrial DNA and polymerase γ, and by its intrinsic 3'→5' exonuclease activity can diminish the polymerization errors. Here we demonstrate the impact of p53 on incorporation of uracil into DNA examined with mitochondrial fractions, as the source of polymerase γ. p53 in mitochondria facilitates DNA damage repair functions resulting from uracil-DNA misincorporation. Our biochemical studies revealed that the procession of U:A and mismatched U:G lesions enhances in the presence of recombinant or endogenous cytoplasmic p53. p53 in mitochondria can function as an exonuclease/proofreader for polymerase γ by either decreasing the incorporation of non-canonical dUTP into DNA or by promoting the excision of incorporated nucleotide from nascent DNA, thus expanding the spectrum of DNA damage sites exploited for proofreading as a transacting protein. The data suggest that p53 may contribute to defense of the cells from consequences of dUTP misincorporation in both normal and tumor cells.

Original languageEnglish
Pages (from-to)73323-73336
Number of pages14
JournalOncotarget
Volume7
Issue number45
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • DNA synthesis
  • Exonuclease
  • Mitochondria
  • P53
  • Uracil

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