DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations

Abstract

DNA polymerase gamma is the only known DNA polymerase in human mitochondria and is essential for mitochondrial DNA replication and repair. It is well established that defects in mtDNA replication lead to mitochondrial dysfunction and disease. Over 160 coding variations in the gene encoding the catalytic subunit of DNA polymerase gamma (POLG) have been identified. Our group and others have characterized a number of the more common and interesting mutations, as well as those disease mutations in the DNA polymerase gamma accessory subunit. We review the results of these studies, which provide clues to the mechanisms leading to the disease state.

Figure 1

The mitochondrion and some of the enzymes involved in mtDNA replication or nucleotide metabolism. Mutations in some of these genes (green boxes) are associated with mtDNA depletion or mutations in humans.

Figure 2

Schematic linear organization of the pol γ catalytic subunit with conserved domains. The conserved 3′-5′ exonuclease domains (orange) are encoded by the three motifs I, II, and III while the DNA polymerase domains (green) are encoded by the three ABC motifs.

Figure 3

POLG disease mutations and polymorphisms (modified from http://tools.niehs.nih.gov/polg/)

Figure 4

POLG disease mutations and their location within the structural homology model of the polymerase domain of pol γ against the solved crystal structure of T7 DNA polymerase [17].

Figure 5

An overview of what is currently known about POLG mutations from experimental studies.