Saccharomyces cerevisiae Ogg1 prevents poly(GT) tract instability in the mitochondrial genome

Vongsamphanh, Ratsavarinh; Wagner, J. Richard; Ramotar, Dindial

doi:10.1016/j.dnarep.2005.10.003

Cited by 11 publications

(5 citation statements)

References 43 publications

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“…The exact role of MMR in mammals is also unclear, as the MutS␤ complex does not bind GO mismatches at all and the MutS␣ complex does not bind or repair GO mismatches efficiently unless the mismatches are within repeats and are associated with slippage (26,30,33). Consistent with these in vitro data, oxidative lesions have been linked to frameshifts and microsatellite instability in many species (13,21,57). Interestingly, human cells lacking Pol were recently shown to have increased rates of spontaneous fragile-site instability (44).…”

Section: Discussionsupporting

confidence: 71%

The Polymerase η Translesion Synthesis DNA Polymerase Acts Independently of the Mismatch Repair System To Limit Mutagenesis Caused by 7,8-Dihydro-8-Oxoguanine in Yeast

Mudrak

Welz-Voegele²,

Jinks-Robertson

2009

Molecular and Cellular Biology

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Reactive oxygen species are ubiquitous mutagens that have been linked to both disease and aging. The most studied oxidative lesion is 7,8-dihydro-8-oxoguanine (GO), which is often miscoded during DNA replication, resulting specifically in GC 3 TA transversions. In yeast, the mismatch repair (MMR) system repairs GO ⅐ A mismatches generated during DNA replication, and the polymerase (Pol) translesion synthesis DNA polymerase additionally promotes error-free bypass of GO lesions. It has been suggested that Pol limits GO-associated mutagenesis exclusively through its participation in the filling of MMR-generated gaps that contain GO lesions. In the experiments reported here, the SUP4-o forward-mutation assay was used to monitor GC 3 TA mutation rates in strains defective in MMR (Msh2 or Msh6) and/or in Pol activity. The results clearly demonstrate that Pol can function independently of the MMR system to prevent GO-associated mutations, presumably through preferential insertion of cytosine opposite replication-blocking GO lesions. Furthermore, the Pol-dependent bypass of GO lesions is more efficient on the lagging strand of replication and requires an interaction with proliferating cell nuclear antigen. These studies establish a new paradigm for the prevention of GO-associated mutagenesis in eukaryotes.Eukaryotic genome stability can be compromised by changes at the nucleotide level, alterations in chromosome structure, or changes in chromosome number. Although such changes are responsible for many human diseases, including cancer, a low level of instability is necessary to provide the raw material for evolutionary processes. Changes at the nucleotide level generally occur during replication, either as errors made when copying an undamaged DNA template or during the bypass of DNA lesions. Many types of DNA lesions are due to reactive oxygen species (ROS), which are generated by exposure to physical and chemical mutagens, as well as by normal metabolic processes, such as aerobic respiration (12, 32). Although cells contain multiple antioxidants and other proteins that protect the genome from oxidative damage, ROS have been implicated as causal agents of many diseases and of aging (11,50).The most common oxidized DNA lesion is 7,8-dihydro-8-oxoguanine, which is referred to here as a GO lesion. The mutagenic potential of this lesion is due to miscoding during DNA synthesis, with replicative DNA polymerases usually misinserting adenine across from the lesion to generate GO ⅐ A mispairs and ultimately GC 3 TA transversions (49). Studies examining the crystal structure of T7 DNA polymerase complexed with a GO ⅐ C base pair or a GO ⅐ A mispair indicate the basis of this mutagenic specificity. Whereas the GO ⅐ C structure physically resembles that of a mismatch, the GO ⅐ A mispair structurally resembles a normal Watson-Crick base pair and therefore is likely to escape polymerase-associated proofreading activity (6). A GO-containing nucleotide triphosphate (8-oxo-dGTP) can also be used by DNA polymerases during DNA synthesis,...

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Section: Discussionsupporting

confidence: 71%

The Polymerase η Translesion Synthesis DNA Polymerase Acts Independently of the Mismatch Repair System To Limit Mutagenesis Caused by 7,8-Dihydro-8-Oxoguanine in Yeast

Mudrak

Welz-Voegele²,

Jinks-Robertson

2009

Molecular and Cellular Biology

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“…ROS-related DNA lesions, including those induced by exogenous H 2 O 2 treatment, are mutagenic, and anaerobic growth conditions reduce their mutagenic effects, such as point mutations and poly(GT) tract instability (13,27,(32)(33)(34)(35). The work presented here demonstrates that reduced oxygen metabolism significantly reduces the rate of spontaneous GCRs in WT strains and tsa1 as well as other mutants and that treatment with H 2 O 2 substantially induces GCRs, indicating that the ROS-induced DNA lesions are an important source of GCRs.…”

Section: Discussionmentioning

confidence: 99%

Oxygen metabolism and reactive oxygen species cause chromosomal rearrangements and cell death

Ragu

Faye

Iraqui

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The absence of Tsa1, a key peroxiredoxin that functions to scavenge H2O2 in Saccharomyces cerevisiae, causes the accumulation of a broad spectrum of mutations including gross chromosomal rearrangements (GCRs). Deletion of TSA1 also causes synthetic lethality in combination with mutations in RAD6 and several key genes involved in DNA double-strand break repair. In the present study we investigated the causes of GCRs and cell death in these mutants. tsa1-associated GCRs were independent of the activity of the translesion DNA polymerases , , and Rev1. Anaerobic growth reduced substantially GCR rates of WT and tsa1 mutants and restored the viability of tsa1 rad6, tsa1 rad51, and tsa1 mre11 double mutants. Anaerobic growth also reduced the GCR rate of rad27, pif1, and rad52 mutants, indicating a role of reactive oxygen species in GCR formation in these mutants. In addition, deletion of TSA1 or H 2O2 treatment of WT cells resulted in increased formation of Rad52 foci, sites of repair of multiple DNA lesions. H 2O2 treatment also induced the GCRs. Our results provide in vivo evidence that oxygen metabolism and reactive oxygen species are important sources of DNA damages that can lead to GCRs and lethal effects in S. cerevisiae.dsDNA break ͉ gross chromosomal rearrangement ͉ translesion DNA synthesis ͉ peroxiredoxin M aintaining genome stability is crucial for cell growth and cell survival. Different genetic disorders, including most human cancers, are associated with different forms of genome instability (1-3). One type of genomic instability observed frequently in many cancers is gross chromosomal rearrangements (GCRs), such as translocations, deletions of chromosome arms, interstitial deletions, inversions, amplifications, chromosome fusions, and aneuploidy. Multiple genes and pathways that suppress GCRs have been characterized by using the yeast Saccharomyces cerevisiae as a model system (4-6). These include genes involved in DNA replication, recombination, and repair, cell-cycle checkpoints that function during DNA replication and repair, and pathways involved in telomere maintenance, chromatin assembly, and detoxification of reactive oxygen species (ROS) (refs. 7 and 8 and references therein). The importance of these pathways for suppressing genome instability is further emphasized by their roles in preventing the development of human cancer (7, 9, 10).Although many pathways that function in the suppression of GCRs have been discovered, little is known about the causes and origin of GCRs. It is generally thought that a major cause of DNA damage that leads to mutations is ROS, which are generated as a normal part of oxygen metabolism but are also produced by ionizing radiation, metabolism of exogenous compounds, and pathological processes such as infection and inflammation (11,12). ROS, such as the superoxide radical, H 2 O 2 , and the hydroxyl radical, can attack almost all cell components and can induce many types of DNA damage, including single-stranded DNA breaks and dsDNA breaks (DSB), base and sugar modificat...

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“…“DNA damage and repair processes can alter DNA structure” below and in [142]. Interestingly, Ogg1 deficiency in yeast mitochondria resulted in an ~six-fold increase in GT repeat deletions as compared to the wild-type, and overexpression of Ogg1 completely suppressed GT repeat deletion events, suggesting that the activity of Ogg-1 could reduce repeat instability mitochondria [143]. In human cells, depletion of OGG-1 by siRNA to 30% of the endogenous levels did not affect the transcription-related CAG repeat instability [108].…”

Section: Dna Repair-related Proteins That Associate With Non-b Dnamentioning

confidence: 99%

The yin and yang of repair mechanisms in DNA structure-induced genetic instability

Vásquez

Wang

2013

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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DNA can adopt a variety of secondary structures that deviate from the canonical Watson-Crick B-DNA form. More than 10 types of non-canonical or non-B DNA secondary structures have been characterized, and the sequences that have the capacity to adopt such structures are very abundant in the human genome. Non-B DNA structures have been implicated in many important biological processes and can serve as sources of genetic instability, implicating them in disease and evolution. Non-B DNA conformations interact with a wide variety of proteins involved in replication, transcription, DNA repair, and chromatin architectural regulation. In this review, we will focus on the interactions of DNA repair proteins with non-B DNA and their roles in genetic instability, as the proteins and DNA involved in such interactions may represent plausible targets for selective therapeutic intervention.

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Saccharomyces cerevisiae Ogg1 prevents poly(GT) tract instability in the mitochondrial genome

Cited by 11 publications

References 43 publications

The Polymerase η Translesion Synthesis DNA Polymerase Acts Independently of the Mismatch Repair System To Limit Mutagenesis Caused by 7,8-Dihydro-8-Oxoguanine in Yeast

The Polymerase η Translesion Synthesis DNA Polymerase Acts Independently of the Mismatch Repair System To Limit Mutagenesis Caused by 7,8-Dihydro-8-Oxoguanine in Yeast

Oxygen metabolism and reactive oxygen species cause chromosomal rearrangements and cell death

The yin and yang of repair mechanisms in DNA structure-induced genetic instability

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