DNA Polymerase θ Increases Mutational Rates in Mitochondrial DNA

Simon Wisnovsky, Tanja Sack, David J. Pagliarini, Rebecca R. Laposa*, Shana O. Kelley

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Replication and maintenance of mitochondrial DNA (mtDNA) is essential for cellular function, yet few DNA polymerases are known to function in mitochondria. Here, we conclusively demonstrate that DNA polymerase θ (Polθ) localizes to mitochondria and explore whether this protein is overexpressed in patient-derived cells and tumors. Polθ appears to play an important role in facilitating mtDNA replication under conditions of oxidative stress, and this error-prone polymerase was found to introduce mutations into mtDNA. In patient-derived cells bearing a pathogenic mtDNA mutation, Polθ expression levels were increased, indicating that the oxidative conditions in these cells promote higher expression levels for Polθ. Heightened Polθ expression levels were also associated with elevated mtDNA mutation rates in a selected panel of human tumor tissues, suggesting that this protein can influence mutational frequencies in tumors. The results reported indicate that the mitochondrial function of Polθ may have relevance to human disease.

Original languageEnglish (US)
Pages (from-to)900-908
Number of pages9
JournalACS chemical biology
Volume13
Issue number4
DOIs
StatePublished - Apr 20 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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