Suppression of gene amplification and chromosomal DNA integration by the DNA mismatch repair system

Nucleic Acids Res. 2001 Aug 15;29(16):3304-10. doi: 10.1093/nar/29.16.3304.

Abstract

Mismatch repair (MMR)-deficient cells are shown to produce >15-fold more methotrexate-resistant colonies than MMR normal cells. The increased resistance to methotrexate is primarily due to gene amplification since all the resistant clones contain double-minute chromosomes and increased copy numbers of the DHFR gene. In addition, integration of linearized or retroviral DNAs into chromosomes is also significantly elevated in MMR-deficient cells. These results suggest that in addition to microsatellite instability and homeologous recombination, MMR is also involved in suppression of other genome instabilities such as gene amplification and chromosomal DNA integration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Base Pair Mismatch / genetics*
  • Carrier Proteins
  • Chromosomes, Human / genetics*
  • Chromosomes, Human / metabolism
  • DNA / genetics
  • DNA / metabolism*
  • DNA Repair / genetics
  • DNA Repair / physiology*
  • Drug Resistance
  • Gene Amplification / drug effects
  • Gene Amplification / genetics*
  • Gene Dosage
  • Genes, Duplicate / genetics
  • Humans
  • Methotrexate / pharmacology
  • Microsatellite Repeats / genetics
  • Moloney murine leukemia virus / genetics
  • MutL Protein Homolog 1
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins
  • Recombination, Genetic / genetics
  • Sequence Homology
  • Tetrahydrofolate Dehydrogenase / genetics
  • Transfection
  • Tumor Cells, Cultured
  • Virus Integration / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • DNA
  • Tetrahydrofolate Dehydrogenase
  • MutL Protein Homolog 1
  • Methotrexate