Fidelity of the Human Mitochondrial DNA Polymerase

The study quantified the fidelity of human mitochondrial DNA polymerase (Pol γ), finding an average error rate of 1 in 440,000 nucleotides. Misincorporation rates varied, with the highest being 1 in 3,563 nucleotides for dGTP:T mismatches and the lowest being 1 in 2.3 million nucleotides for dCTP:C mismatches. The enzyme's role in maintaining mitochondrial DNA integrity was emphasized, given the higher mutation rates in mitochondrial DNA and its link to degenerative diseases. The study also noted that base pair geometry and hydrogen bonding significantly influenced nucleotide incorporation fidelity, with overall fidelity improving to 1 error in 1.8 × 10^6 to 3.6 × 10^7 bases when exonuclease proofreading was included. These findings have potential implications for drug design to reduce toxicity in treatments involving nucleoside analogs.