DNA polymerase proofreading: Multiple roles maintain genome stability

Reha-Krantz, Linda J.

doi:10.1016/j.bbapap.2009.06.012

Cited by 152 publications

(188 citation statements)

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“…POLE encodes the DNA polymerase epsilon, which is responsible for leading strand DNA replication (17,18). POLE high replication fidelity depends, in part, on its 3 0 to 5 0 proofreading abilities (19,20). Early studies of substitutions in DNA polymerases were shown to inactivate or suppress proofreading abilities, thus causing increased replicative error rates (21,22).…”

Section: Introductionmentioning

confidence: 99%

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

McConechy

Talhouk

Leung

et al. 2016

Clinical Cancer Research

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Purpose: The aim of this study was to confirm the prognostic significance of POLE exonuclease domain mutations (EDM) in endometrial carcinoma patients. In addition, the effect of treatment on POLE-mutated tumors was assessed.Experimental Design: A retrospective patient cohort of 496 endometrial carcinoma patients was identified for targeted sequencing of the POLE exonuclease domain, yielding 406 evaluable tumors. Univariable and multivariable analyses were performed to determine the effect of POLE mutation status on progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Combining results from eight studies in a meta-analysis, we computed pooled HR for PFS, DSS, and OS.Results: POLE EDMs were identified in 39 of 406 (9.6%) endometrial carcinomas. Women with POLE-mutated endometrial carcinomas were younger, with stage I (92%) tumors, grade 3 (62%), endometrioid histology (82%), and frequent (49%) lymphovascular invasion. In univariable analysis, POLE-mutated endometrial carcinomas had significantly improved outcomes compared with patients with no EDMs for PFS, DSS, and OS. In multivariable analysis, POLE EDMs were only significantly associated with improved PFS. The effect of adjuvant treatment on POLE-mutated cases could not be determined conclusively; however, both treated and untreated patients with POLE EDMs had good outcomes. Meta-analysis revealed an association between POLE EDMs and improved PFS and DSS with pooled HRs 0.34 [95% confidence interval (CI), 0.15-0.73] and 0.35 (95% CI, 0.13-0.92), respectively.Conclusions: POLE EDMs are prognostic markers associated with excellent outcomes for endometrial carcinoma patients. Further investigation is needed to conclusively determine if treatment is necessary for this group of women.

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Section: Introductionmentioning

confidence: 99%

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

McConechy

Talhouk

Leung

et al. 2016

Clinical Cancer Research

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161

119

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“…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).The remaining Pol e antimutator substitutions affect other domains in the polymerase structure (Figures 4 and 7). V522A maps to the amino domain in an a-helix previously implicated in pol3-01 mutator suppression (Figure 7, A, B, and E) (Herr et al 2011a).…”

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confidence: 99%

“…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).…”

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confidence: 99%

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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“…Although both the pol and exo activities of the DNAP have been studied extensively [35], the distributions of dwell times of DNAP have not been measured so far in any single molecule experiment [36]. In this paper we have also mentioned a few recently developed single-molecule techniques for DNAP [38,37] which, after minor alteration, might be the appropriate tool for measur-ing the conditional dwell times introduced in this paper.…”

Section: Discussionmentioning

confidence: 99%

First-passage problems in DNA replication: effects of template tension on stepping and exonuclease activities of a DNA polymerase motor

Sharma

Chowdhury

2013

J. Phys.: Condens. Matter

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A DNA polymerase (DNAP) replicates a template DNA strand. It also exploits the template as the track for its own motor-like mechanical movement. In the polymerase mode it elongates the nascent DNA by one nucleotide in each step. But, whenever it commits an error by misincorporting an incorrect nucleotide, it can switch to an exonuclease mode. In the latter mode it excises the wrong nucleotide before switching back to its polymerase mode. We develop a stochastic kinetic model of DNA replication that mimics an in-vitro experiment where a single-stranded DNA, subjected to a mechanical tension F , is converted to a double-stranded DNA by a single DNAP. The F -dependence of the average rate of replication, which depends on the rates of both polymerase and exonuclease activities of the DNAP, is in good qualitative agreement with the corresponding experimental results. We introduce 9 novel distinct conditional dwell times of a DNAP. Using the methods of first-passage times, we also derive the exact analytical expressions for the probability distributions of these conditional dwell times. The predicted F -dependence of these distributions are, in principle, accessible to single-molecule experiments.

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DNA polymerase proofreading: Multiple roles maintain genome stability

Cited by 152 publications

References 168 publications

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

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

First-passage problems in DNA replication: effects of template tension on stepping and exonuclease activities of a DNA polymerase motor

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