GENETIC INSTABILITY WITHIN MONOTONOUS RUNS OF CPG SEQUENCES IN ESCHERICHIA-COLI

Genetic information can be altered by base substitutions, frameshift m utations, and addition or deletion of nucleotides. Deletions represent an important class of genetic aberration occurring at DNA sequences w here it is often possible to predict the existence of intermediates of mutation. Instability within tracts of repetitive sequence have recen tly been associated with several genetic disorders, including the so-c alled triplet repeat diseases and certain forms of colorectal cancers. In Escherichia coli, (GpC)(n) repetitive sequences have been shown to be deletion prone, but the precise mechanism of this mutagenic pathwa y is still unknown. We show here that interrupting the monotony of the (GpC)(n) run with an ApT or a GpT dinucleotide decreases the rate of deletions within these sequences. On the other hand, introducing purin e-pyrimidine alternating sequences beside the GpC insert results in an increased rate of deletion. Two pathways can be envisioned: (1) (GpC) (n) tracts can be seen as potential Z-forming DNA sequences, and this unusual DNA structure can be processed by an unknown cellular mechanis m to give rise to the observed deletions and (2) (GpC)(n) monotonous r uns can be considered as a succession of direct or palindromic repeats , allowing formation of DNA structures that are known to participate t o frameshift mutagenesis. The results presented in this article are di scussed in the light of these two alternative pathways.