Overexpression of DNA Polymerase Zeta Reduces the Mitochondrial Mutability Caused by Pathological Mutations in DNA Polymerase Gamma in Yeast

Baruffini, Enrico; Serafini, Fausta; Ferrero, Iliana; Lodi, Tiziana

doi:10.1371/journal.pone.0034322

Cited by 19 publications

(23 citation statements)

References 77 publications

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“…In agreement with in vitro data, genetic studies have demonstrated that yeast pol ζ is not only necessary for damage-induced nuclear and mitochondrial genome mutagenesis, it also promotes accurate bypass of some DNA lesions (Baruffini et al , 2012; Baynton et al , 1999; Bresson and Fuchs, 2002; Kalifa and Sia, 2007; Zhang et al , 2006). On all damaged templates tested, pol ζ was a great deal less efficient at incorporating a nucleotide opposite the damaged bases than extending the resulting primer terminus, consistent with the idea that its primary role in lesion bypass is confined to the elongation step, while the incorporation step depends on other polymerases.…”

Section: Biochemical Properties Of Tls Polymerasessupporting

confidence: 73%

Translesion DNA polymerases in eukaryotes: what makes them tick?

Vaisman

Woodgate

2017

Critical Reviews in Biochemistry and Molecular Biology

211

204

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Life as we know it, simply would not exist without DNA replication. All living organisms utilize a complex machinery to duplicate their genomes and the central role in this machinery belongs to replicative DNA polymerases, enzymes that are specifically designed to copy DNA. “Hassle-free” DNA duplication exists only in an ideal world, while in real life, it is constantly threatened by a myriad of diverse challenges. Among the most pressing obstacles that replicative polymerases often cannot overcome by themselves, are lesions that distort the structure of DNA. Despite elaborate systems that cells utilize to cleanse their genomes of damaged DNA, repair is often incomplete. The persistence of DNA lesions obstructing the cellular replicases can have deleterious consequences. One of the mechanisms allowing cells to complete replication is “Translesion DNA Synthesis (TLS). TLS is intrinsically error-prone, but apparently, the potential downside of increased mutagenesis is a healthier outcome for the cell than incomplete replication. Although most of the currently identified eukaryotic DNA polymerases have been implicated in TLS, the best characterized are those belonging to the “Y-family” of DNA polymerases (pols η, ι, κ, and Rev1), which are thought to play major roles in the TLS of persisting DNA lesions in coordination with the B-family polymerase, pol ζ. In this review, we summarize the unique features of these DNA polymerases by mainly focusing on their biochemical and structural characteristics, as well as potential protein-protein interactions with other critical factors affecting TLS regulation.

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Section: Biochemical Properties Of Tls Polymerasessupporting

confidence: 73%

Translesion DNA polymerases in eukaryotes: what makes them tick?

Vaisman

Woodgate

2017

Critical Reviews in Biochemistry and Molecular Biology

211

204

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“…The same levels of rescue can be achieved by deletion of SML1 , which encodes a protein that inhibits the ribonucleotide reductase activity by binding and sequestering Rnr1 (Chabes et al, 1999 ; Zhao et al, 2000 ). The deletion of SML1 had the same effect of RNR1 overexpression both on the mip1-1 mutant and on the pathological Mip1 variants (Zhao et al, 1998 ; Baruffini et al, 2006 , 2012 ).…”

Section: Mip1 Interactionsmentioning

confidence: 95%

DNA polymerase Î³ and disease: what we have learned from yeast

et al. 2015

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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.

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“…POLG is also able to bypass 8-oxoG and exocyclic DNA adducts that gives rise to increased mutagenicity [112, 113]. Both Polζ and Rev1 have been identified to have a role in yeast mitochondrial genome maintenance where overexpression of these enzymes led to a reduction in point mutations in the mtDNA [114, 115]. More recently, Polζ was detected in the mitochondria of mammalian cells and elevated expression of the enzyme in breast tumors was associated with cell migration and invasion [116].…”

Section: Mitochondrial Dna Genome Maintenancementioning

confidence: 99%

DNA damage related crosstalk between the nucleus and mitochondria

Saki

Prakash

2017

Free Radical Biology and Medicine

127

105

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The electron transport chain is the primary pathway by which a cell generates energy in the form of ATP. Byproducts of this process produce reactive oxygen species that can cause damage to mitochondrial DNA. If not properly repaired, the accumulation of DNA damage can lead to mitochondrial dysfunction linked to several human disorders including neurodegenerative diseases and cancer. Mitochondria are able to combat oxidative DNA damage via repair mechanisms that are analogous to those found in the nucleus. Of the repair pathways currently reported in the mitochondria, the base excision repair pathway is the most comprehensively described. Proteins that are involved with the maintenance of mtDNA are encoded by nuclear genes and translocate to the mitochondria making signaling between the nucleus and mitochondria imperative. In this review, we discuss the current understanding of mitochondrial DNA repair mechanisms and also highlight the sensors and signaling pathways that mediate crosstalk between the nucleus and mitochondria in the event of mitochondrial stress.

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Overexpression of DNA Polymerase Zeta Reduces the Mitochondrial Mutability Caused by Pathological Mutations in DNA Polymerase Gamma in Yeast

Cited by 19 publications

References 77 publications

Translesion DNA polymerases in eukaryotes: what makes them tick?

Translesion DNA polymerases in eukaryotes: what makes them tick?

DNA polymerase Î³ and disease: what we have learned from yeast

DNA damage related crosstalk between the nucleus and mitochondria

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