Microsatellite instability is co-selectable with gene amplification in a mammalian mutator phenotype

The effect of an unbalanced nucleotide pool on the stability of dinucleotide (CA)n microsatellite sequences was investigated in the mutator phenotype CSA7 clone isolated from Chinese hamster CHEF18 cell line. A series of clones isolated from CHEF18 and CSA7 cells and resistant to 6-thioguanine (TG) were shown to be stable at the three examined microsatellite loci. Furthermore, the clones isolated from CHEF18 cells and resistant to N-phosphonacetyl-L-aspartate (PALA) were stable, whereas those isolated from CSA7 clone were unstable. At the biological level the clones with instability did not show tolerance of methylnitrosourea-induced damage, thus excluding the presence of a defective mismatch repair. On the contrary, the molecular characterization showed that the instability, measured as extension or contraction of (CA)n repeats, involved numerous repeats resembling the amplification rather than mutation of the microsatellite loci. The results therefore indicate that the unbalanced nucleotide pool of CSA7 clone influences the overall rate of gene amplification and support that the unstable microsatellites are coselectable with other gene amplification events.