Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer

Eur J Hum Genet. 2011 Mar;19(3):320-5. doi: 10.1038/ejhg.2010.216. Epub 2010 Dec 15.


Genomic sequences encoding the 3' exonuclease (proofreading) domains of both replicative DNA polymerases, pol delta and pol epsilon, were explored simultaneously in human colorectal carcinomas including six established cell lines. Three unequivocal sequence alterations, including one previously reported, were found, and all these were considered as dysfunctional mutations in light of the local amino-acid sequences. In particular, the F367S mutation found in the POLE gene encoding the pol epsilon catalytic subunit, which includes the proofreading domain, is the first found in human diseases. Surprisingly, the tumours carrying these proofreading domain mutations were all defective in DNA mismatch repair (MMR). In addition to the two cell lines with acknowledged MMR gene mutations, the third tumour was also demonstrated to harbour a distinct mutation in MLH1, and indeed exhibited a microsatellite-unstable phenotype. These findings suggest that, in concert with MMR deficiency, defective polymerase proofreading may also contribute to the mutator phenotype observed in human colorectal cancer. Our observations may suggest previously unrecognised complexities in the molecular abnormalities underlying the mutator phenotype in human neoplasms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Amino Acid Sequence
  • Colorectal Neoplasms / genetics*
  • DNA Mismatch Repair*
  • DNA Polymerase II / genetics*
  • DNA Polymerase III / genetics*
  • DNA Replication
  • Exonucleases / genetics
  • Exonucleases / metabolism
  • Female
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • Mutation*
  • Nuclear Proteins / genetics
  • Phenotype
  • Poly-ADP-Ribose Binding Proteins
  • Sequence Analysis, DNA


  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • Nuclear Proteins
  • Poly-ADP-Ribose Binding Proteins
  • DNA Polymerase II
  • DNA Polymerase III
  • POLE protein, human
  • Exonucleases
  • spleen exonuclease
  • MutL Protein Homolog 1