Selection for genome instability by DNA damage in human cells: unstable microsatellites and their consequences for tumourigenesis.
The emergence of tumour cells resistant to chemotherapeutic treatment is a major confounding factor in anticancer treatment. Many chemotherapeutic drugs are DNA damaging agents. Resistance to DNA damage can be acquired via a plethora of different mechanisms, including, surprisingly, loss of DNA mismatch repair activity. The DNA mismatch repair system acts after DNA replication and corrects non-Watson-Crick base pairs and other replication errors. Human cells lacking mismatch repair activity have high spontaneous mutation rates. Frequent frameshift mutations in repetitive DNA sequences are characteristically associated with the defect. This hypermutability at repetitive sequences is termed microsatellite instability. DNA mismatch repair defects underlie a predisposition to cancer and are associated with a significant fraction of apparently sporadic cancer cases. In contrast to many other neoplasms, gross genetic aberrations are rare in cells from tumours with microsatellite instability. In these mismatch repair-defective tumours, certain genes that would normally hinder tumour development are frequently found to be inactivated by frameshift mutations in repetitive DNA tracts within their coding sequences. This implies that the small-scale genome alterations characteristic of mismatch repair defects can act as a driving force in tumour development.
Hampson
R
R
Imperial Cancer Research Fund, Clare Hall Laboratories, Hertsfordsbire, United Kingdom. hampson@icrf.icnet.uk
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001482:Base Composition; D001483:Base Sequence; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D010641:Phenotype; D012091:Repetitive Sequences, Nucleic Acid; D012307:Risk Factors
D000970:Antineoplastic Agents