Antimutator variants of DNA polymerases

Herr, Alan J.; Williams, Lindsey N.; Preston, Bradley D.

doi:10.3109/10409238.2011.620941

Cited by 24 publications

(29 citation statements)

References 182 publications

(321 reference statements)

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“…Similar to the yeast variants that we describe (data herein and Herr et al 2011a), E. coli antimutators were isolated in the absence of native proofreading and are due to individual amino-acid substitutions throughout the polymerase structures (Schaaper 1998;Loh et al 2007;Herr et al 2011b). Accordingly, Schaaper and colleagues proposed two general mechanisms for polymerase antimutators: (1) increased dNTP discrimination and (2) increased dissociation from DNA to allow editing by alternate pathways (Fijalkowska and Schaaper 1995).…”

Section: Perspectives and Conclusionmentioning

confidence: 98%

“…Previous studies identified antimutator variants of bacteriophage T4 and E. coli DNA polymerases (reviewed in RehaKrantz 1995;Schaaper 1998;Herr et al 2011b). Similar to the yeast variants that we describe (data herein and Herr et al 2011a), E. coli antimutators were isolated in the absence of native proofreading and are due to individual amino-acid substitutions throughout the polymerase structures (Schaaper 1998;Loh et al 2007;Herr et al 2011b).…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

“…Studies of T4 antimutators show that enhanced discrimination against some errors is commonly accompanied by weakened discrimination against others (Drake 1993). Polymerase variants with increased fidelity often have reduced overall activity (Loh et al 2007), which can improve accuracy (Clayton et al 1979;Kunkel et al 1994;Joyce and Benkovic 2004;Johnson 2010;Herr et al 2011b), but will also increase error rates for some mutation types (Kunkel et al 1994) and may trigger mutagenic replication processes in the cell (Northam et al 2006;Aksenova et al 2010;Northam et al 2010). Additionally, T850M and K966Q would increase mutagenesis if they hamper partitioning of nascent errors to the exonuclease active site (Donlin et al 1991;Reha-Krantz 2010).…”

Section: Escape From Pol E Error-induced Extinctionmentioning

confidence: 99%

“…Thus, mutations in DUN1 are unlikely eex candidates. There are a number of other possible antimutagenesis mechanisms involving multiple pathways and candidate genes (Herr et al 2011b). Whole-genome sequencing should greatly facilitate identification of the chromosomal eex alleles (Birkeland et al 2010;Wenger et al 2010;Dunham 2012).…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

“…Thus, following adaptation, selection pressure favors restoration of low mutation rates, which can occur through the elimination of mutator alleles or the acquisition of mutator suppressors (i.e., antimutators). A limited number of antimutator variants in the DNA replication machinery have been described (reviewed in Herr et al 2011b). …”

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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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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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Section: Perspectives and Conclusionmentioning

confidence: 98%

Section: Perspectives and Conclusionmentioning

confidence: 99%

Section: Escape From Pol E Error-induced Extinctionmentioning

confidence: 99%

Section: Perspectives and Conclusionmentioning

confidence: 99%

mentioning

confidence: 99%

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

2013

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DNA polymerase delta in dna replication and genome maintenance

Prindle

Loeb

2012

Environ and Mol Mutagen

120

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The eukaryotic genome is in a constant state of modification and repair. Faithful transmission of the genomic information from parent to daughter cells depends upon an extensive system of surveillance, signaling, and DNA repair, as well as accurate synthesis of DNA during replication. Often, replicative synthesis occurs over regions of DNA that have not yet been repaired, presenting further challenges to genomic stability. DNA polymerase δ (Pol δ) occupies a central role in all of these processes: catalyzing the accurate replication of a majority of the genome, participating in several DNA repair synthetic pathways, and contributing structurally to the accurate bypass of problematic lesions during translesion synthesis. The concerted actions of pol δ on the lagging strand, pol ε on the leading strand, associated replicative factors, and the mismatch repair (MMR) proteins results in a mutation rate of less than one misincorporation per genome per replication cycle. This low mutation rate provides a high level of protection against genetic defects during development and may prevent the initiation of malignancies in somatic cells. This review explores the role of Pol δ in replication fidelity and genome maintenance.

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DNA polymerase ε and its roles in genome stability

Henninger

Pursell

2014

IUBMB Life

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DNA Polymerase Epsilon (Pol e) is one of three DNA Polymerases (along with Pol d and Pol a) required for nuclear DNA replication in eukaryotes. Pol e is comprised of four subunits, the largest of which is encoded by the POLE gene and contains the catalytic polymerase and exonuclease activities. The 3 0 -5 0 exonuclease proofreading activity is able to correct DNA synthesis errors and helps protect against genome instability. Recent cancer genome sequencing efforts have shown that 3% of colorectal and 7% of endometrial cancers contain mutations within the exonuclease domain of POLE and are associated with significantly elevated levels of single nucleotide substitutions (15-500 per Mb) and microsatellite stability. POLE mutations have also been found in other tumor types, though at lower frequency, suggesting roles in tumorigenesis more broadly in different tissue types. In addition to its proofreading activity, Pol e contributes to genome stability through multiple mechanisms that are discussed in this review.

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Antimutator variants of DNA polymerases

Cited by 24 publications

References 182 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

DNA polymerase delta in dna replication and genome maintenance

DNA polymerase ε and its roles in genome stability

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