Base analog 6-N-hydroxylaminopurine mutagenesis in the yeast Saccharomyces cerevisiae is controlled by replicative DNA polymerases

Shcherbakova, Polina V.; Noskov, Vladimir N.; Pshenichnov, M. R.; Pavlov, Youri I.

doi:10.1016/s0165-1218(96)90045-2

Cited by 45 publications

(41 citation statements)

References 29 publications

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“…Both polymerases are accurate and possess intrinsic proofreading exonucleases that edit mispaired primer termini during polymerization (Morrison et al 1991;Simon et al 1991;Shimizu et al 2002;Shcherbakova et al 2003;Fortune et al 2005). Defects in Pol e or Pol d proofreading increase the spontaneous mutation rate in a manner consistent with major roles for these polymerases in leadingand lagging-strand synthesis (Morrison et al 1991;Simon et al 1991;Morrison and Sugino 1994;Shcherbakova et al 1996;Tran et al 1999;Karthikeyan et al 2000;Greene and Jinks-Robertson 2001). Interestingly, the Pol d proofreading defect generates a mutator phenotype 5-to 30-fold greater than that observed in Pol e proofreading-deficient strains (Morrison and Sugino 1994;Shcherbakova et al 1996;Tran et al 1999;Datta et al 2000;Karthikeyan et al 2000;Greene and Jinks-Robertson 2001;Pavlov et al 2004), and the spectra of spontaneous mutations that arise in Pol e and Pol d proofreading-deficient strains differ, which may reflect distinct error specificities of the polymerases as well as strand-specific effects (Morrison and Sugino 1994;Karthikeyan et al 2000;Pavlov et al 2002Pavlov et al , 2003Shcherbakova et al 2003;Fortune et al 2005).…”

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confidence: 70%

“…Defects in Pol e or Pol d proofreading increase the spontaneous mutation rate in a manner consistent with major roles for these polymerases in leadingand lagging-strand synthesis (Morrison et al 1991;Simon et al 1991;Morrison and Sugino 1994;Shcherbakova et al 1996;Tran et al 1999;Karthikeyan et al 2000;Greene and Jinks-Robertson 2001). Interestingly, the Pol d proofreading defect generates a mutator phenotype 5-to 30-fold greater than that observed in Pol e proofreading-deficient strains (Morrison and Sugino 1994;Shcherbakova et al 1996;Tran et al 1999;Datta et al 2000;Karthikeyan et al 2000;Greene and Jinks-Robertson 2001;Pavlov et al 2004), and the spectra of spontaneous mutations that arise in Pol e and Pol d proofreading-deficient strains differ, which may reflect distinct error specificities of the polymerases as well as strand-specific effects (Morrison and Sugino 1994;Karthikeyan et al 2000;Pavlov et al 2002Pavlov et al , 2003Shcherbakova et al 2003;Fortune et al 2005). Mouse cells with defects in Pol e or Pol d proofreading also exhibit increased mutation rates (Goldsby et al 2002;Albertson et al 2009), and, consistent with distinct roles in DNA replication, the types of tumors that develop in Pol e and Pol d proofreading-deficient mice differ markedly (Albertson et al 2009).…”

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confidence: 70%

“…This pattern of abortive growth typifies cells undergoing replication error-induced extinction (Morrison et al 1993;Herr et al 2011a). Pols z and h do not mediate pol2-4 msh2D synthetic lethalityThe mutator phenotypes of many DNA replication mutants are dependent on the specialized DNA polymerase Pol z (Shcherbakova et al 1996;Pavlov et al 2001; Kai and Wang Figure 1 Genetic interactions between Pol e and Pol d proofreading and MMR. Using a plasmid-shuffling strategy, proofreading-deficient variants of Pol e (encoded by pol2-4) or Pol d (encoded by pol3-01) or wild-type controls (POL2 or POL3) were introduced via LEU2 plasmids into BY4733 pol2D or pol3D strains harboring deletion mutations that partially (A) or completely (B) abrogate MMR.…”

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confidence: 99%

“…As previously suggested (Shcherbakova et al 2003), Pols e and d may replicate similar amounts of the yeast genome, but may do so with different accuracies, perhaps by utilizing strand-or polymerase-specific accessory factors or repair pathways that decrease mutations from Pol e or by triggering the mutagenic Dun1 pathway that increases mutations from Pol d (Datta et al 2000;Reha-Krantz et al 2011). Interestingly, the error-prone DNA polymerases z and h do not significantly impact mutagenesis by proofreading-deficient Pol e or Pol d (Figure 2) (Shcherbakova et al 1996;Datta et al 2000). Additional studies are required to examine in greater detail the roles of Pol e and Pol d in vivo and the pathways that mediate mutagenesis when these polymerases err.…”

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Emergence of DNA Polymerase ε Antimutators That Escape Error-Induced Extinction in Yeast

2013

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DNA polymerases (Pols) e and d perform the bulk of yeast leading-and lagging-strand DNA synthesis. Both Pols possess intrinsic proofreading exonucleases that edit errors during polymerization. Rare errors that elude proofreading are extended into duplex DNA and excised by the mismatch repair (MMR) system. Strains that lack Pol proofreading or MMR exhibit a 10-to 100-fold increase in spontaneous mutation rate (mutator phenotype), and inactivation of both Pol d proofreading (pol3-01) and MMR is lethal due to replication error-induced extinction (EEX). It is unclear whether a similar synthetic lethal relationship exists between defects in Pol e proofreading (pol2-4) and MMR. Using a plasmid-shuffling strategy in haploid Saccharomyces cerevisiae, we observed synthetic lethality of pol2-4 with alleles that completely abrogate MMR (msh2D, mlh1D, msh3D msh6D, or pms1D mlh3D) but not with partial MMR loss (msh3D, msh6D, pms1D, or mlh3D), indicating that high levels of unrepaired Pol e errors drive extinction. However, variants that escape this error-induced extinction (eex mutants) frequently emerged. Five percent of pol2-4 msh2D eex mutants encoded second-site changes in Pol e that reduced the pol2-4 mutator phenotype between 3-and 23-fold. The remaining eex alleles were extragenic to pol2-4. The locations of antimutator amino-acid changes in Pol e and their effects on mutation spectra suggest multiple mechanisms of mutator suppression. Our data indicate that unrepaired leading-and lagging-strand polymerase errors drive extinction within a few cell divisions and suggest that there are polymerase-specific pathways of mutator suppression. The prevalence of suppressors extragenic to the Pol e gene suggests that factors in addition to proofreading and MMR influence leading-strand DNA replication fidelity.O RGANISMS must accurately duplicate their genomes to avoid loss of long-term fitness. Consequently, cells employ high-fidelity DNA polymerases (Pols) equipped with proofreading exonucleases to replicate their DNA (reviewed in McCulloch and Kunkel 2008;Reha-Krantz 2010). Mismatch repair (MMR) further ensures the integrity of genetic information by targeting mismatches for excision from newly replicated DNA (reviewed in Kolodner and Marsischky 1999;Iyer et al. 2006;Hsieh and Yamane 2008). These polymerase error-correcting mechanisms, together with DNA damage repair (Friedberg et al. 2006), maintain the genome with less than one mutation per 10 9 nucleotides per cell division (Drake et al. 1998). Defects in proofreading or MMR result in mutator phenotypes characterized by increased rates of spontaneous mutation (Kolodner and Marsischky 1999;Iyer et al. 2006;Hsieh and Yamane 2008;McCulloch and Kunkel 2008; RehaKrantz 2010).Mutator phenotypes can be an important source of genetic diversity, which facilitates adaptation to environmental change. In bacterial and yeast populations, unstable environments favor mutator strains that readily acquire adaptive mutations (Chao and Cox 1983;Mao et al. 1997;Sniegowski et al. 1997...

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confidence: 70%

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confidence: 99%

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Emergence of DNA Polymerase ε Antimutators That Escape Error-Induced Extinction in Yeast

2013

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“…Error-prone synthesis by Pol ζ and Pol η allows bypass of replication-blocking DNA lesions (46), and several mutator polymerases are known to create mutations in a Pol ζ-dependent manner (47)(48)(49)(50)(51)(52). To test whether Pol ζ or Pol η lies downstream of Dun1 and contributes to the pol2 mutator phenotypes, we engineered pol2-4 and pol2-M644G strains lacking Pol ζ (rev3Δ) or Pol η (rad30Δ).…”

Section: Dun1 Is Required For the Mutator Phenotype Or Viability Of Pol2mentioning

confidence: 99%

dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants

Williams

Marjavaara

Knowels

et al. 2015

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

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Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) e mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol e depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol e proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol e base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Δ but not rad9Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol e mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy.DNA replication and repair | polymerase fidelity | cancer | lethal mutagenesis

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Modulation of mutagenesis in eukaryotes by DNA replication fork dynamics and quality of nucleotide pools

Waisertreiger

Liston

Menezes

et al. 2012

Environ and Mol Mutagen

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The rate of mutations in eukaryotes depends on a plethora of factors and is not immediately derived from the fidelity of DNA polymerases (Pols). Replication of chromosomes containing the anti-parallel strands of duplex DNA occurs through the copying of leading and lagging strand templates by a trio of Pols α, δ and ε, with the assistance of Pol ζ and Y-family Pols at difficult DNA template structures or sites of DNA damage. The parameters of the synthesis at a given location are dictated by the quality and quantity of nucleotides in the pools, replication fork architecture, transcription status, regulation of Pol switches, and structure of chromatin. The result of these transactions is a subject of survey and editing by DNA repair.

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Base analog 6-N-hydroxylaminopurine mutagenesis in the yeast Saccharomyces cerevisiae is controlled by replicative DNA polymerases

Cited by 45 publications

References 29 publications

Emergence of DNA Polymerase ε Antimutators That Escape Error-Induced Extinction in Yeast

Emergence of DNA Polymerase ε Antimutators That Escape Error-Induced Extinction in Yeast

dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants

Modulation of mutagenesis in eukaryotes by DNA replication fork dynamics and quality of nucleotide pools

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