REPAIR-MODIFICATION OF RADIODAMAGED GENES

It is proposed that through repair-modification, the modified base 5mC may have facilitated the divergent evolution of coding (hypomethylate d exon) and uncoding (hypermethylated promoter and intron) sequences i n eukaryotic genes. The radioinduced repair patches appearing in regio ns lacking 5mC are fully reconstructed by excision-repair, whereas tho se appearing in regions containing 5mC are incompletely reconstructed by this conventional mechanism. Such a second class of repair patches may, however, become fully reconstructed, in the S phase, by repair-mo dification. In fact, while DNA polymerase beta - which is a key enzyme of excision-repair - is active through the whole interphase. DNA meth ylase - which is responsible for post synthetic DNA modification - is essentially active in S. Uncoupling of these two enzyme systems, outsi de S, might explain why in unsynchronised cells repair patches of non- replicating strands are hypomethylated when compared with specific met hylation of replicating strands. In other words, excision-repair would always be able to re-establish the primary ATGC language of both dama ged unmethylated and methylated regions, while repair-modification wou ld be able to re-establish the modified ATGC(5mC) language of the dama ged methylated regions, only in S, but not in G(1) or G(2). In these t wo phases, when DNA methylation is inversely correlated with pre-mRNA transcription (as in the case of many tissue-specific genes), such dem ethylation might induce a silent transcriptional unit to become active .