Intragenomic heterogeneity of DNA damage formation and repair: a review of cellular responses to covalent drug DNA interaction.

Chemical DNA interaction and its processing can now be studied at the level of specific genomic regions. Such investigations have revealed important new information about the molecular biology of the cellular responses to genomic insult and especially of the repair processes. They also have demonstrated that both the formation and repair of DNA damage display patterns of intragenomic heterogeneity. Therefore, mechanistic studies should involve examination of DNA damage formation and repair in specific genomic sequences besides in the overall genome to provide clues to the way in which specific modifications of DNA or chromatin could have specific biological effects. This review primarily focuses on studies done to elucidate the nature of DNA damage induction and intragenomic processing provoked by covalent drug-DNA modification in mammalian cells. The involvement of DNA damage formation and cellular processing as critical factors for genomic injury is exemplified by studies of the novel alkylating morpholinyl anthracyclines and the bifunctional alkylating agent nitrogen mustard as a prototype agent for covalent drug DNA interaction.