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

Lodi T, Dallabona C, Nolli C, Goffrini P, Donnini C, Baruffini E - Front Genet (2015)

Bottom Line: It belongs to the family A of the DNA polymerases and it is orthologs to human POLGA.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, University of Parma Parma, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: 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 then, in which mip1 alleles carrying substitutions corresponding to pathological mutations were expressed in mutant strains devoid of mtDNA polymerase, as explained later. Besides studies designed to validate the pathogenicity of human mutations and to understand the molecular mechanisms responsible for the associated diseases, studies performed in yeast led to the discovery of the genetic and chemical rescue of the effects of mutations in MIP1, through ribonucleotide reductase overexpression and the administration of antioxidants, respectively (Baruffini et al., 2006). These observations led to several studies on human cells or murine organisms. At the same time, with the help of yeast, pharmacogenetic research was performed in order to study the correlation between toxicity due to sodium valproate or NRTIs, and polymorphisms in POLG (Baruffini and Lodi, 2010; Stewart et al., 2010). The milestones described in this chapter are illustrated in Figure 1.


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

Lodi T, Dallabona C, Nolli C, Goffrini P, Donnini C, Baruffini E - Front Genet (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362329&req=5

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.
Mentions: 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 then, in which mip1 alleles carrying substitutions corresponding to pathological mutations were expressed in mutant strains devoid of mtDNA polymerase, as explained later. Besides studies designed to validate the pathogenicity of human mutations and to understand the molecular mechanisms responsible for the associated diseases, studies performed in yeast led to the discovery of the genetic and chemical rescue of the effects of mutations in MIP1, through ribonucleotide reductase overexpression and the administration of antioxidants, respectively (Baruffini et al., 2006). These observations led to several studies on human cells or murine organisms. At the same time, with the help of yeast, pharmacogenetic research was performed in order to study the correlation between toxicity due to sodium valproate or NRTIs, and polymorphisms in POLG (Baruffini and Lodi, 2010; Stewart et al., 2010). The milestones described in this chapter are illustrated in Figure 1.

Bottom Line: It belongs to the family A of the DNA polymerases and it is orthologs to human POLGA.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, University of Parma Parma, Italy.

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.

No MeSH data available.


Related in: MedlinePlus