Modeling of pathogenic variants of mitochondrial DNA polymerase: insight into the replication defects and implication for human disease

Hoyos-Gonzalez, Nallely; Trasviña-Arenas, Carlos H.; Degiorgi, Andrea; Castro-Lara, Atzimaba Y.; Peralta-Castro, Antolín; Jiménez‐Sandoval, Pedro; Díaz‐Quezada, Corina; Lodi, Tiziana; Baruffini, Enrico; Brieba, Luis G.

doi:10.1016/j.bbagen.2020.129608

Cited by 4 publications

(3 citation statements)

References 52 publications

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“…in vitro biochemical studies performed on mutant Mip1 variant purified from yeast or other organisms such as E. coli showed that mutations can affect the function of Mip1 in several ways: some mutations reduced protein stability, especially at higher temperatures, other mutations reduce polymerase activity, processivity, DNA binding affinity, affinity for the incoming dNTPs or the specific constant, whereas other mutations cause an increase in the exo/pol ratio. In most cases, the exonuclease activity was not or slightly decreased, even in the case of mutations in the exonuclease domain, indicating that the defects of mtDNA replication are not due to defects of the proofreading activity 61,63,70 Several mutations located in the palm and in the fingers subdomains are dominant when modeled in yeast, as their human counterparts.…”

Section: Yeast As a Model For Studying Polg‐related Disordersmentioning

confidence: 99%

“…Interestingly, several mutations in the exonuclease domain strongly increased the petite frequency or result in the total loss of mtDNA, indicating that the exonuclease domain is fundamental for a proper replication process and to avoid deletions/depletion. The exceptions are the mutations located in the N‐terminal extension and in the palm C‐terminal extension, which behave as neutral polymorphisms; however, just two mutations have been introduced in these regions, due to the low degree of conservation between human Pol γ and Mip1 62,63 . In addition, human p.Ala467Thr mutation, the most frequent variant found in humans and recognized as pathological, 64 behaved like a neutral mutation in yeast; this discrepancy could be explained by the fact that Ala467 is involved in the interaction with the accessory subunit, which is absent in yeast, suggesting another role for the corresponding amino acid Ile 416 58 …”

Section: Yeast As a Model For Studying Polg‐related Disordersmentioning

confidence: 99%

“…In most cases, the exonuclease activity was not or slightly decreased, even in the case of mutations in the exonuclease domain, indicating that the defects of mtDNA replication are not due to defects of the proofreading activity. 61,63,70 vii. Several mutations located in the palm and in the fingers subdomains are dominant when modeled in yeast, as their human counterparts.…”

Section: Analysis Of Human Pathological Mutations In a Yeast Modelmentioning

confidence: 99%

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The Saccharomyces cerevisiae mitochondrial DNA polymerase and its contribution to the knowledge about human POLG‐related disorders

Gilea,

Magistrati,

Notaroberto

et al. 2023

IUBMB Life

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Most eukaryotes possess a mitochondrial genome, called mtDNA. In animals and fungi, the replication of mtDNA is entrusted by the DNA polymerase γ, or Pol γ. The yeast Pol γ is composed only of a catalytic subunit encoded by MIP1. In humans, Pol γ is a heterotrimer composed of a catalytic subunit homolog to Mip1, encoded by POLG, and two accessory subunits. In the last 25 years, more than 300 pathological mutations in POLG have been identified as the cause of several mitochondrial diseases, called POLG‐related disorders, which are characterized by multiple mtDNA deletions and/or depletion in affected tissues. In this review, at first, we summarize the biochemical properties of yeast Mip1, and how mutations, especially those introduced recently in the N‐terminal and C‐terminal regions of the enzyme, affect the in vitro activity of the enzyme and the in vivo phenotype connected to the mtDNA stability and to the mtDNA extended and point mutability. Then, we focus on the use of yeast harboring Mip1 mutations equivalent to the human ones to confirm their pathogenicity, identify the phenotypic defects caused by these mutations, and find both mechanisms and molecular compounds able to rescue the detrimental phenotype. A closing chapter will be dedicated to other polymerases found in yeast mitochondria, namely Pol ζ, Rev1 and Pol η, and to their genetic interactions with Mip1 necessary to maintain mtDNA stability and to avoid the accumulation of spontaneous or induced point mutations.

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Section: Yeast As a Model For Studying Polg‐related Disordersmentioning

confidence: 99%

Section: Yeast As a Model For Studying Polg‐related Disordersmentioning

confidence: 99%

Section: Analysis Of Human Pathological Mutations In a Yeast Modelmentioning

confidence: 99%

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The Saccharomyces cerevisiae mitochondrial DNA polymerase and its contribution to the knowledge about human POLG‐related disorders

Gilea,

Magistrati,

Notaroberto

et al. 2023

IUBMB Life

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Exploring the molecular aspect and updating evolutionary approaches to the DNA polymerase enzymes for biotechnological needs: A comprehensive review

Laatri,

El Khayari,

Qriouet

2024

International Journal of Biological Macromolecules

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The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

Berti

Punzio

Dallabona

et al. 2021

Genes

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The increasing application of next generation sequencing approaches to the analysis of human exome and whole genome data has enabled the identification of novel variants and new genes involved in mitochondrial diseases. The ability of surviving in the absence of oxidative phosphorylation (OXPHOS) and mitochondrial genome makes the yeast Saccharomyces cerevisiae an excellent model system for investigating the role of these new variants in mitochondrial-related conditions and dissecting the molecular mechanisms associated with these diseases. The aim of this review was to highlight the main advantages offered by this model for the study of mitochondrial diseases, from the validation and characterisation of novel mutations to the dissection of the role played by genes in mitochondrial functionality and the discovery of potential therapeutic molecules. The review also provides a summary of the main contributions to the understanding of mitochondrial diseases emerged from the study of this simple eukaryotic organism.

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Modeling of pathogenic variants of mitochondrial DNA polymerase: insight into the replication defects and implication for human disease

Cited by 4 publications

References 52 publications

The Saccharomyces cerevisiae mitochondrial DNA polymerase and its contribution to the knowledge about human POLG‐related disorders

The Saccharomyces cerevisiae mitochondrial DNA polymerase and its contribution to the knowledge about human POLG‐related disorders

Exploring the molecular aspect and updating evolutionary approaches to the DNA polymerase enzymes for biotechnological needs: A comprehensive review

The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

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