Diseases of DNA Polymerase Gamma

Polymerase gamma (Polγ) is the DNA-dependent DNA polymerase responsible for replicating mitochondrial DNA. The enzyme is a trimer and comprises one catalytic subunit (POLG), which contains the polymerase activity together with proofreading exonuclease activity, and two accessory subunits (POLG2) that promote DNA binding and processivity. Replication of mtDNA requires several additional proteins: in vitro studies have shown that the minimal replication machinery consists of the helicase Twinkle, mitochondrial RNA polymerase and single-stranded binding protein [1], but others may be required in vivo [2]. Mutations in POLG are one of the most common causes of mitochondrial disease and responsible for a wide range of phenotypes. Mutations in POLG2 are rare. Disease caused by mutations in Twinkle gives a similar spectrum of disease to those caused by POLG and we will discuss them together where this is appropriate.