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.

Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy

“…Interestingly, in P1 fibroblasts we observed a reduced amount of mtDNA compared with controls. This result parallelizes with the findings in yeast, where the presence of the mutation Ser39Gly was associated with an increase in cytoplasmic petite colonies, a phenotype that reflects depletion or large scale deletions of mtDNA [Lodi et al., ].…”

Mitochondrial Genome Variation Affects Multiple Respiration and Nonrespiration Phenotypes in Saccharomyces cerevisiae

“…the 500-1500 member mitochondrial proteome is nuclearly encoded (Steinmetz et al 2002a;Sickmann et al 2003;Perocchi et al 2008;Rhee et al 2013). Thus, S. cerevisiae is an excellent model for studies of human mitochondrial and nuclear-mitochondrial gene product functions (Steinmetz et al 2002a;Schwimmer et al 2006;Perocchi et al 2008;Baile and Claypool 2013;Rutter and Hughes 2015), as well as for nuclear-mitochondrial pathogenic polymorphisms (Stumpf and Copeland 2011;Montanari et al 2013;Kabala et al 2014;Lodi et al 2015).…”

Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer

“…The other currently observed breast cancer associating variant, POLG p.L392V, was relatively common in the analyzed cohorts and showed twofold enrichment in the breast cancer cases, indicating a moderate effect on disease predisposition. POLG p.L392V affects an evolutionarily highly conserved residue in the exonuclease domain of the protein that is responsible for the proofreading activity during mtDNA replication . Accurate replication of mtDNA is highly important for the cells, since several mitochondrial genes encode proteins crucial for the cellular energy production through oxidative phosphorylation (OXPHOS).…”