Review
DNA replication fidelity and cancer

https://doi.org/10.1016/j.semcancer.2010.10.009Get rights and content

Abstract

Cancer is fueled by mutations and driven by adaptive selection. Normal cells avoid deleterious mutations by replicating their genomes with extraordinary accuracy. Here we review the pathways governing DNA replication fidelity and discuss evidence implicating replication errors (point mutation instability or PIN) in carcinogenesis.

Section snippets

Genetic instability and cancer

Tumor development is a multistep process requiring the accumulation of mutations that activate oncogenes or inactivate tumor suppressors [1], [2], [3]. To maintain normal cell functions, genetic stability is strictly controlled [4]. Therefore it is argued that defects in pathways governing genetic stability will facilitate tumorigenesis by fueling the reiterative process of mutation, selection and clonal expansion that drives cancer progression (reviewed and debated in [5], [6], [7], [8], [9],

Determinants of DNA replication fidelity

Normal cells replicate their DNA with extraordinary fidelity (∼10−10 mutations per base pair per cell division) [52]. This is achieved through the combined actions of polymerase base selectivity, 3′ → 5′ exonucleolytic proofreading, mismatch correction and DNA damage repair (Fig. 1; reviewed in [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71]).

Proofreading and MMR both contribute substantially to the overall fidelity of cellular DNA

Mutator mice

Although mechanisms of DNA replication fidelity have been studied extensively in simple microbes, less is known about the corresponding pathways and their functions in higher eukaryotes. Mammals require faithful DNA replication to avoid deleterious mutations in critical subpopulations of cells (gametes, stem cells, and developing embryos) and to sustain essential somatic functions throughout the adult reproductive life span. At the same time, increased mutation (hypermutation) is required for

Pol δ and ɛ mutations in human cancer

The studies of Pol δ and ɛ proofreading-deficient mice underscore the importance of DNA polymerase fidelity in the suppression of spontaneous tumorigenesis. It is reasonable to speculate that polymerase mutator alleles also increase the risk of human cancers [200], [201]. The mouse studies suggest roles for Pol ɛ mutators in the genesis of intestinal tumors and Pol δ mutators in skin and lung carcinogenesis. Pol ɛ and δ mutators are also implicated in hematologic malignancies, and aggressive

Summary and perspectives

At the beginning of the 20th century, cytogenetic techniques revealed the first chromosomal abnormalities in malignant cells and led to the hypothesis that genetic instability fueled cancer [230], [231]. Since then it has become clear that multiple changes in the genome, including point mutations, insertion/deletion events, large chromosomal rearrangements and epigenetic modifications of gene expression dysregulate cellular pathways on the road to malignant transformation [1], [2], [3], [13],

Conflicts of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

Our sincere thanks go to Larry Loeb for his critical insight and creative spirit. We also thank past and present laboratory members for valuable discussions and experimental contributions. Our research was supported by the National Institutes of Health (R01 ES09927, R01 CA098243, R01 CA111582, P20 CA103728, P01 AG01751 and P01 CA77852) and the National Institute of Environmental Health Sciences-sponsored Center for Ecogenetics and Environmental Health at the University of Washington (P30 ES07033

References (240)

  • R.D. Kolodner et al.

    Eukaryotic DNA mismatch repair

    Curr Opin Genet Dev

    (1999)
  • P. Hsieh et al.

    DNA mismatch repair: molecular mechanism, cancer, and ageing

    Mech Ageing Dev

    (2008)
  • S.A. Nick McElhinny et al.

    Division of labor at the eukaryotic replication fork

    Mol Cell

    (2008)
  • T.A. Kunkel et al.

    Dividing the workload at a eukaryotic replication fork

    Trends Cell Biol

    (2008)
  • M. Meuth

    The molecular basis of mutations induced by deoxyribonucleoside triphosphate pool imbalances in mammalian cells

    Exp Cell Res

    (1989)
  • B.A. Kunz et al.

    Deoxyribonucleoside triphosphate levels: a critical factor in the maintenance of genetic stability

    Mutat Res

    (1994)
  • T. Tajiri et al.

    Functional cooperation of MutT, MutM and MutY proteins in preventing mutations caused by spontaneous oxidation of guanine nucleotide in Escherichia coli

    Mutat Res

    (1995)
  • M.T. Russo et al.

    Different DNA repair strategies to combat the threat from 8-oxoguanine

    Mutat Res

    (2007)
  • B. Vogelstein et al.

    Cancer genes and the pathways they control

    Nat Med

    (2004)
  • R.A. Weinberg

    The biology of cancer

    (2007)
  • R.D. Kolodner et al.

    Maintenance of genome stability in Saccharomyces cerevisiae

    Science

    (2002)
  • P.C. Nowell

    The clonal evolution of tumor cell populations

    Science

    (1976)
  • L.A. Loeb et al.

    Errors in DNA replication as a basis of malignant changes

    Cancer Res

    (1974)
  • L.A. Loeb et al.

    Cancers exhibit a mutator phenotype: clinical implications

    Cancer Res

    (2008)
  • W. Bodmer

    Genetic instability is not a requirement for tumor development

    Cancer Res

    (2008)
  • R.T. Prehn

    Cancers beget mutations versus mutations beget cancers

    Cancer Res

    (1994)
  • D.P. Cahill et al.

    Genetic instability and Darwinian selection in tumours

    Trends Cell Biol

    (1999)
  • G.R. Anderson et al.

    Cancer: the evolved consequence of a destabilized genome

    Bioessays

    (2001)
  • N. Beerenwinkel et al.

    Genetic progression and the waiting time to cancer

    PLoS Comput Biol

    (2007)
  • S. Negrini et al.

    Genomic instability—an evolving hallmark of cancer

    Nat Rev Mol Cell Biol

    (2010)
  • C. Lengauer et al.

    Genetic instabilities in human cancers

    Nature

    (1998)
  • Special Issue on Genome Instability

    Science

    (2002)
  • Special Issue on Genome Instability

    Nat Rev Mol Cell Biol

    (2010)
  • F. Mitelman et al.

    The impact of translocations and gene fusions on cancer causation

    Nat Rev Cancer

    (2007)
  • F. Mitelman et al.

    Mitelman database of chromosome aberrations and gene fusions in cancer

    (2010)
  • T.D. Tlsty et al.

    Differences in the rate of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria–Delbruk fluctuation analysis

    Proc Natl Acad Sci USA

    (1989)
  • G. Phear et al.

    Loss of heterozygosity and base substitution at the APRT locus in mismatch repair-proficient and -deficient colorectal carcinoma cell lines

    Mol Cell Biol

    (1996)
  • C. Lengauer et al.

    Genetic instability in colorectal cancers

    Nature

    (1997)
  • J.H. Hoeijmakers

    Genome maintenance mechanisms for preventing cancer

    Nature

    (2001)
  • J.E. Cleaver et al.

    Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity

    Nat Rev Genet

    (2009)
  • J.H. Bielas et al.

    Human cancers express a mutator phenotype

    Proc Natl Acad Sci USA

    (2006)
  • C.A. Klein

    Random mutations, selected mutations: a PIN opens the door to new genetic landscapes

    Proc Natl Acad Sci USA

    (2006)
  • H.T. Lynch et al.

    Hereditary colorectal cancer

    N Engl J Med

    (2003)
  • A. de la Chapelle

    Genetic predisposition to colorectal cancer

    Nat Rev Cancer

    (2004)
  • W.M. Abdel-Rahman et al.

    Lynch syndrome and related familial colorectal cancers

    Crit Rev Oncog

    (2008)
  • H.T. Lynch et al.

    Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

    Clin Genet

    (2009)
  • C.R. Boland et al.

    Microsatellite instability in colorectal cancer

    Gastroenterology

    (2010)
  • C.E. Bronner et al.

    Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer

    Nature

    (1994)
  • N. Papadopoulos et al.

    Mutation of a mutL homolog in hereditary colon cancer

    Science

    (1994)
  • P. Peltomaki et al.

    Mutations associated with HNPCC predisposition—update of ICG-HNPCC/INSiGHT mutation database

    Dis Markers

    (2004)

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