Mutations of an intronic repeat induce impaired MRE11 expression in primary human cancer with microsatellite instability

Oncogene. 2004 Apr 8;23(15):2640-7. doi: 10.1038/sj.onc.1207409.


Frequent mutations of coding nucleotide repeats are thought to contribute significantly to carcinogenesis associated with microsatellite instability (MSI). We have shown that shortening of the poly(T)11 within the polypyrimidine stretch/accessory splicing signal of human MRE11 leads to the reduced expression and functional impairment of the MRE11/NBS1/RAD50 complex. This mutation was selectively found in mismatch repair (MMR) defective cell lines and potentially identifies MRE11 as a novel target for MSI. Here, we examined 70 microsatellite unstable primary human cancers and we report that MRE11 mutations occur in 83.7 and 50% of the colorectal and endometrial cancers, respectively. In the colorectal cancer series, mutated MRE11 is more frequently associated with advanced age at diagnosis and A/B stages. Biallelic mutations were present in 38.8% of the cases and more frequently associated with lower (G1/G2) grade tumors. Impaired MRE11 expression was prevalent in primary colorectal tumors with larger and biallelic shortening of the poly(T)11. Immunohistochemistry confirmed the impaired MRE11 expression and revealed NBS1-defective expression in MRE11 mutated cancers. Together with the observation that perturbation of the MRE11/NBS1/RAD50 complex predisposes to cancer, our work highlights MRE11 as a new common target in the MMR deficient tumorigenesis and suggests its role in colorectal carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Base Pair Mismatch
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics*
  • Cell Line
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • DNA Repair
  • DNA Sequence, Unstable
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Endodeoxyribonucleases / biosynthesis*
  • Endodeoxyribonucleases / genetics*
  • Exodeoxyribonucleases / biosynthesis*
  • Exodeoxyribonucleases / genetics*
  • Exons
  • Female
  • Humans
  • Immunohistochemistry
  • Introns
  • Male
  • Microsatellite Repeats*
  • Middle Aged
  • Mutation*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / biosynthesis*
  • Saccharomyces cerevisiae Proteins / genetics*
  • Tumor Cells, Cultured


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • NBN protein, human
  • Nuclear Proteins
  • RAD50 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Endodeoxyribonucleases
  • Exodeoxyribonucleases
  • MRE11 protein, S cerevisiae