Clonally derived cell lines with altered DNA methylation as models for error correction and mutation in tumours

We have investigated the relative importance of DNA methylation-directed repair of replication errors to the production of mutation/gene rearrangements in mammalian cells with hypomethylated genomes. Using a series of sibling (Chinese hamster derived) cell clones with stably altered DNA methylation levels, we found that genomic hypomethylation was frequently associated with an elevated spontaneous mutation rate in the hypoxanthine phosphoribosyl transferase (HPRT) gene and with increased sensitivity to 2-aminopurine, a known inducer of DNA base mismatches. However, while there are some alterations in sites of DNA methylation around the HPRT gene, there was no systematic direction of change to differentiate between cells with normal or with elevated mutation rates. Further, the nature of gene alterations giving rise to the HPRT mutations suggested that methylation-directed mismatch repair is of little if any significance in influencing error avoidance in mammalian cells with hypomethylated genomes and that increased mutation associated with DNA hypomethylation is more likely to be due to increased genomic instability through activation of such factors as transposable elements.