Title
Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites
Author
Irina G. Minko, Aaron C. Jacobs, Arnie R. de Leon, Francesca Gruppi, Nathan Donley, Thomas M. Harris, Carmelo J. Rizzo, Amanda K. McCullough, R. Stephen Lloyd
Year
2016
Journal
Scientific Reports
Abstract
Apurinic/apyrimidinic (AP) sites are constantly formed in cellular DNA due to instability of the glycosidic bond, particularly at purines and various oxidized, alkylated, or otherwise damaged nucleobases. AP sites are also generated by DNA glycosylases that initiate DNA base excision repair. These lesions represent a significant block to DNA replication and are extremely mutagenic. Some DNA glycosylases possess AP lyase activities that nick the DNA strand at the deoxyribose moiety via a β- or β,δ-elimination reaction. Various amines can incise AP sites via a similar mechanism, but this non-enzymatic cleavage typically requires high reagent concentrations. Herein, we describe a new class of small molecules that function at low micromolar concentrations as both β- and β,δ-elimination catalysts at AP sites. Structure-activity relationships have established several characteristics that appear to be necessary for the formation of an iminium ion intermediate that self-catalyzes the elimination at the deoxyribose ring.
Full Article
Instrument
J-810
Keywords
Circular dichroism, DNA structure, Ligand binding, Biochemistry