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.
Highlights
DNA polymerase γ is the only DNA replicase identified in animal and fungal mitochondria
Since both nuclear and mitochondrial genomes participate to oxidative phosphorylation (OXPHOS) functions, Saccharomyces cerevisiae DNA polymerase γ the petite phenotype can derive from mutations in nuclear genes that encode mitochondrial functions or from mitochondrial DNA (mtDNA) mutations
In 2014, Qian and coauthors constructed a “humanized” yeast model in which yeast Mip1 was replaced by human polymerase γ (Pol γ)
Summary
DNA polymerase γ (or Pol γ) is the only DNA replicase identified in animal and fungal mitochondria. Thanks to its ability to grow even in the absence of mitochondrial DNA and to the sequence conservation among eukaryotic polymerase γ, yeast was considered to be the organism of choice to study the effects of pathological mutations in human Pol γ, starting from 2006 (Stuart et al, 2006), a few years after the first identification of pathological mutation in the POLG gene (Van Goethem et al, 2001) Several works have been published since in which mip alleles carrying substitutions corresponding to pathological mutations were expressed in mutant strains devoid of mtDNA polymerase, as explained later.
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