DNA polymerase γ and disease: what we have learned from yeast

Abstract

Mip1 is the Saccharomyces cerevisiae DNA polymerase γ (Pol γ), which is responsible for the replication of mitochondrial DNA (mtDNA). It belongs to the family A of the DNA polymerases and it is orthologs to human POLGA. In humans, mutations in POLG(1) cause many mitochondrial pathologies, such as progressive external ophthalmoplegia (PEO), Alpers' syndrome, and ataxia-neuropathy syndrome, all of which present instability of mtDNA, which results in impaired mitochondrial function in several tissues with variable degrees of severity. In this review, we summarize the genetic and biochemical knowledge published on yeast mitochondrial DNA polymerase from 1989, when the MIP1 gene was first cloned, up until now. The role of yeast is particularly emphasized in (i) validating the pathological mutations found in human POLG and modeled in MIP1, (ii) determining the molecular defects caused by these mutations and (iii) finding the correlation between mutations/polymorphisms in POLGA and mtDNA toxicity induced by specific drugs. We also describe recent findings regarding the discovery of molecules able to rescue the phenotypic defects caused by pathological mutations in Mip1, and the construction of a model system in which the human Pol γ holoenzyme is expressed in yeast and complements the loss of Mip1.

Keywords: DNA polymerase γ; Mip1; Mip1 interactions; Pol γ mutations; yeast model.

Figure 1

Mip1 milestones. Information regarding yeast Mip1 is shown in blue, information on other eukaryotic Pol γ obtained thanks to the use of yeast Mip1 is in red, information on human POLGA mutations/polymorphisms obtained by modeling and studying the mutations in yeast is in green.

Figure 2

Domains of human POLGA and yeast Mip1 shown in linear form. Linear form of human POLGA according to its 3D structure. The linear form of Mip1 was constructed following the alignment of yeast Mip1 and human POLGA. MLS, mitochondrial localization signal; Exo, exonuclease domain; Spacer, spacer or linker region; Pol, polymerase domain; MTS, mitochondrial targeting sequence; CTE, C-terminal extension.