Mutagens contribute to the human burden of heritable birth defects and cancer and probably to heart disease as well. Mutagenic DNA damage usually consists of lesions that block DNA replication. Error-prone repair, the major mechanism of damage-induced mutagenesis, occurs when DNA replication bypasses such damaged bases in a poorly templated (and thus highly mutagenic) manner. Replication blocks have been studied in vitro but hardly at all in vivo. We are establishing systems to map, at the nucleotide level, those sites at which mammalian replication forks terminate synthesis synthesis when replicating damaged DNA and to analyze the relationship between DNA blocking lesions and mutation-prone sites.
