DNA polymerase gamma, the mitochondrial replicase

Annu Rev Biochem. 2004;73:293-320. doi: 10.1146/annurev.biochem.72.121801.161455.


DNA polymerase (pol) gamma is the sole DNA polymerase in animal mitochondria. Biochemical and genetic evidence document a key role for pol gamma in mitochondrial DNA replication, and whereas DNA repair and recombination were thought to be limited or absent in animal mitochondria, both have been demonstrated in recent years. Thus, the mitochondrial replicase is also apparently responsible for the relevant DNA synthetic reactions in these processes. Pol gamma comprises a catalytic core in a heterodimeric complex with an accessory subunit. The two-subunit holoenzyme is an efficient and processive polymerase, which exhibits high fidelity in nucleotide selection and incorporation while proofreading errors with its intrinsic 3' 5' exonuclease. Incorporation of nucleotide analogs followed by proofreading failure leads to mitochondrial toxicity in antiviral therapy, and misincorporation during DNA replication leads to mitochondrial mutagenesis and dysfunction. This review describes our current understanding of pol gamma biochemistry and biology, and it introduces other key proteins that function at the mitochondrial DNA replication fork.

Publication types

  • Historical Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • DNA Polymerase gamma
  • DNA Replication
  • DNA-Directed DNA Polymerase / chemistry*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / history
  • DNA-Directed DNA Polymerase / metabolism*
  • Exonucleases / chemistry
  • Exonucleases / genetics
  • Exonucleases / metabolism
  • History, 20th Century
  • Humans
  • Mitochondria / enzymology*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis
  • Protein Subunits
  • Sequence Homology, Amino Acid


  • Protein Subunits
  • DNA replicase
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • Exonucleases