Polymerase gamma becomes a mutator polymerase, accelerating the accumulation of point mutations, frameshifts, and deletions in mitochondrial DNA. The steady accumulation of mutations is what accounts for the late onset and progressive nature of PEO. As a result, researchers now know that an errant DNA polymerase can cause disease.
It is unexpected news. "Polymerases are so essential, it was predicted long ago that no one would ever see natural mutations affecting fidelity," says Copeland. Reducing fidelity was presumed lethal. But if a mutator polymerase were possible, it would be a mutant polymerase gamma, Copeland believed, reasoning that the hundreds, sometimes thousands, of copies of mitochondrial DNA (mtDNA) inside cells provided a margin of safety against accumulating mutations. Even as mutator polymerases inactivated one gene after another, plenty of undamaged mitochondria would remain to permit normal cellular function.
The experiments, led by Mikhail V. Ponamarev, studied catalytic rate, binding affinity, replication ...
