The entire nucleotide sequence of the genome must be transmitted from one generation to the next with no or few errors. Preservation of this integrity requires multiple genes whose alteration can lead to an early event in tumorigenesis by increasing the mutation rate. This mutator phenotype would provide a continuing pool of mutants upon which selection could act to promote a tumor. Recent evidence consistant with this hypothesis is the mutator phenotype of tumor cells of patients with a hereditary form of colon cancer (HNPCC) which exhibit a several hundred-fold increase in spontaneous mutations in addition to a high degree of microsatellite instability. The multiple genomic alterations increasingly reported as associated with most cancers may therefore be linked to a variety of DNA metabolic processes guardians of the genome, including fidelity of the DNA synthesis and mismatch repair. The connection between cancer and deregulation of nucleotide synthesis, imbalance of the pools of nucleotides, deficiency of DNA polymerases, and mismatch repair is the subject of this review. We consider how perturbation in these DNA transactions results in instability of the genome and cancer.

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