DNA Polymerase Gamma (γ)

The DNA polymerase γ (Pol- γ) is an enzyme responsible for the replication and repair of the mitochondrial genome in eukaryote cells, and despite being a mitochondrial enzyme it is coded by nuclear genes.

This enzyme, in humans for example, is a 195 kDa heterotrimer, made up of one catalytic subunit (coded by the gene POLG, situated in chromosome 15q25 – long arm of chromosome 15, region 2, band 2) and an dimeric accessory subunit (coded by the gene POLG2 situated in the chromosome 17q- long arm of chromosome 17). The catalytic subunit possesses only one exonuclease activity that is the 5’-3’ exonuclease activity (proofreading) and a 5’dRP lyase activity, that is the feature responsible for the repair of nucleotide base pairs, by the base excision repair mechanism. The accessory subunit  acts as a DNA binding factor that confers high processivity by increasing the enzyme’s affinity for template DNA.  DNA polymerase γ has a high base-substitution fidelity and is relatively precise for short repeat sequences but longer homopolymer segments tend to yield replication slippage by DNA polymerase γ.

Unlike nuclear DNA, that only replicates during cell division, mitochondrial DNA is continually being recycled, independently of the cell cycle, and as such, mutations in the genes responsible for the coding of the DNA Polymerase γ will have drastic consequences in the individuals where those mutations occur.  For example, mutations that lead to a loss of the DNA polymerase γ exonuclease activity (mutation on the POLG gene) will lead to a much more accelerated aging, this because the mitochondrial genome codes for 13 polypeptide subunits of the respiratory chain. If the respiratory chain is compromised, the flow of electrons will yeld free radicals that will contribute to a greater cell oxidation, and beyond that the ATP formation will be also compromised. This phenomenon’s are responsible, for example, the Alper’s disease.

   

The DNA polymerase γ activity is still poorly understood, however it is known that the Nuclear Respiratory factor-1 (NRF-1) is a transcription factor that regulates the expression of many mitochondrial proteins, by binding to promoter regions of POLG, POLG2 and mtTFA (mitochondrial transcription factor). The binding of NRF-1 is related to the ATP levels.