Jerome J. Solomon

Modifying nucleic acids is believed to be the first step in initiating the multi-step carcinogenic process. Mutations are believed to result from specific DNA adducts. Assessing the biological consequences of specific adducts will advance our understanding of somatic mutagenesis. We recently discovered a new class of DNA adducts, 3-hydroxyalkyl uracil residues, which are cytosine alkylation products that undergo a rapid hydrolytic deamination to form a uracil lesion by various environmentally important mutagenic and carcinogenic aliphatic epoxides including ethylene oxide (EO), propylene oxide (PO), and the epoxide of acrylonitrile. 3-Hydroxyalkyl uracil is a potentially mutagenic lesion occupying a central Watson-Crick hydrogen-bonding position and likely to disrupt normal base-pairing. We believe that 3-hydroxyalkyl uracil may be the critical premutagenic lesion produced by aliphatic epoxides in vivo.

We proposed a mechanism (see Figure) involving intramolecular catalysis by the hydroxyl group. We also demonstrated that PO induces mutations at template cytosine residues and that synthesized oligomers containing a single 3-hydroxyethyl uracil lesion induced by EO can be mutagenically bypassed during in vitro DNA polymerization. Our future investigations will focus on the formation and persistence of this lesion in vivo and determine its mutagenic consequences using a site-specific mutagenesis assay in human cells. This research will provide a clearer understanding of the molecular mechanisms relative to how carcinogenesis starts with an environmentally significant class of carcinogens for which the mechanism of somatic mutagenesis is unknown.