Suppression of gene amplification and chromosomal DNA integration by the DNA mismatch repair system.
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.
Lin
C T
CT
National Health Research Institute, Cancer Research Division, Cooperative Laboratory, Veterans General Hospital, 201 Shih-Pai Road, Sec. 2, Taipei 112, Taiwan, Republic of China. linct@nhri.org.tw
Lyu
Y L
YL
Xiao
H
H
Lin
W H
WH
Whang-Peng
J
J
D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch / Q000235:genetics*; D002352:Carrier Proteins; D002877:Chromosomes, Human / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004351:Drug Resistance; D005784:Gene Amplification / Q000187:drug effects / Q000235:genetics*; D018628:Gene Dosage; D020131:Genes, Duplicate / Q000235:genetics; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D018895:Microsatellite Repeats / Q000235:genetics; D008979:Moloney murine leukemia virus / Q000235:genetics; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D011995:Recombination, Genetic / Q000235:genetics; D017385:Sequence Homology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D016662:Virus Integration / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D004247:DNA; D013762:Tetrahydrofolate Dehydrogenase; D000070957:MutL Protein Homolog 1; D008727:Methotrexate