O⁶‐Alkylguanine DNA Alkyltransferase Mediated Disassembly of a DNA Tetrahedron

Abstract

Tetrahedron DNA structures were formed by the assembly of three‐way junction (TWJ) oligonucleotides containing O6‐2′‐deoxyguanosine‐alkylene‐O6‐2′‐deoxyguanosine (butylene and heptylene linked) intrastrand cross‐links (IaCLs) lacking a phosphodiester group between the 2′‐deoxyribose residues. The DNA tetrahedra containing TWJs were shown to undergo an unhooking reaction by the human DNA repair protein O6‐alkylguanine DNA alkyltransferase (hAGT) resulting in structure disassembly. The unhooking reaction of hAGT towards the DNA tetrahedra was observed to be moderate to virtually complete depending on the protein equivalents. DNA tetrahedron structures have been explored as drug delivery platforms that release their payload in response to triggers, such as light, chemical agents or hybridization of release strands. The dismantling of DNA tetrahedron structures by a DNA repair protein contributes to the armamentarium of approaches for drug release employing DNA nanostructures.