Products Generated by Amine-Catalyzed Strand Cleavage at Apurinic/Apyrimidinic Sites in DNA: New Insights from a Biomimetic Nucleoside Model System

Abasic sites are common in cellular and synthetic DNA. As a result, it is important to characterize the chemical fate of these lesions. Amine-catalyzed strand cleavage at abasic sites in DNA is an important process in which conversion of small amounts of the ring-opened abasic aldehyde residue to an iminium ion facilitates beta-elimination of the 3'-phosphoryl group. This reaction generates a trans-alpha,beta-unsaturated iminium ion on the 3'-terminus of the strand break as an obligate intermediate. The canonical product expected from amine-catalyzed cleavage at an AP site is the corresponding trans-alpha,beta-unsaturated aldehyde sugar remnant resulting from hydrolysis of this iminium ion. Interestingly, a handful of studies have reported noncanonical 3'-sugar remnants generated by amine-catalyzed strand cleavage, but the formation and properties of these products are not well-understood. To address this knowledge gap, a nucleoside system was developed that enabled chemical characterization of the sugar remnants generated by amine-catalyzed beta-elimination in the 2-deoxyribose system. The results predict that amine-catalyzed strand cleavage at an AP site under physiological conditions has the potential to reversibly generate noncanonical cleavage products including cis-alkenal, 3-thio-2,3-dideoxyribose, and 2-deoxyribose groups alongside the canonical trans-alkenal residue on the 3'-terminus of the strand break. Thus, the model reactions provide evidence that the products generated by amine-catalyzed strand cleavage at abasic sites in cellular DNA may be more complex that commonly thought, with trans-alpha,beta-unsaturated iminium ion intermediates residing at the hub of interconverting product mixtures. The results expand the list of possible 3'-sugar remnants arising from amine-catalyzed cleavage of abasic sites in DNA that must be chemically or enzymatically removed for the completion of base excision repair and single-strand break repair in cells.