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DNA polymerase epsilon and delta proofreading suppress discrete mutator and cancer phenotypes in mice.

Organisms require faithful DNA replication to avoid deleterious mutations. In yeast, replicative leading- and lagging-strand DNA polymerases (Pols epsilon and delta, respectively) have intrinsic proofreading exonucleases that cooperate with each other and mismatch repair to limit spontaneous mutation to less than 1 per genome per cell division. The relationship of these pathways in mammals and their functions in vivo are unknown. Here we show that mouse Pol epsilon and delta proofreading suppress discrete mutator and cancer phenotypes. We found that inactivation of Pol epsilon proofreading elevates base-substitution mutations and accelerates a unique spectrum of spontaneous cancers; the types of tumors are entirely different from those triggered by loss of Pol delta proofreading. Intercrosses of Pol epsilon-, Pol delta-, and mismatch repair-mutant mice show that Pol epsilon and delta proofreading act in parallel pathways to prevent spontaneous mutation and cancer. These findings distinguish Pol epsilon and delta functions in vivo and reveal tissue-specific requirements for DNA replication fidelity.

Pubmed ID: 19805137


  • Albertson TM
  • Ogawa M
  • Bugni JM
  • Hays LE
  • Chen Y
  • Wang Y
  • Treuting PM
  • Heddle JA
  • Goldsby RE
  • Preston BD


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

October 6, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: K08 CA72731
  • Agency: NIA NIH HHS, Id: P01 AG01751
  • Agency: NCI NIH HHS, Id: P01 CA77852
  • Agency: NIEHS NIH HHS, Id: P30 ES07033
  • Agency: NCI NIH HHS, Id: R01 CA098243
  • Agency: NCI NIH HHS, Id: R01 CA111582
  • Agency: NIEHS NIH HHS, Id: R01 ES09927
  • Agency: NIEHS NIH HHS, Id: U01 ES11045

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Base Sequence
  • DNA Polymerase II
  • DNA Polymerase III
  • Female
  • Gene Expression Profiling
  • Gene Frequency
  • Genotype
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • MutS Homolog 2 Protein
  • Mutation
  • Neoplasms
  • Nuclear Proteins
  • Phenotype
  • Reverse Transcriptase Polymerase Chain Reaction