Sequence specificity of DNA cleavage by Bis(1,10-phenanthroline)copper(I): Effects of single base pair transitions on the cleavage of preferred pyrimidine-purine-pyrimidine triplets

The cleavage of DNA restriction fragments by bis(1,10-phenanthroline)copper(I) [[(OP)2CuI]+] is sequence dependent: the trimer TAT is most strongly preferred, while the trimer TGT and tetramers TAAT, TAGT, and CAGT are strongly to moderately preferred. [(OP)2CuI]+ cleavage of a series of oligonucleotide duplexes of the type 5'-CCCTPyPuPyCCCC-3'/3'-GGGAPuPyPuGGGG-5' (Py = pyrimidine; Pu = purine) was examined to determine the effects of purine substituents in the central triplet on specificity. The relative cleavage rates of different PyPuPy triplets in oligomers were similar to those observed for restriction fragments. The undecamer duplex containing the trimer TAT (TTATC) was most preferentially cleaved, predominantly at the central adenosine and the adjacent 3'-thymidine. Duplexes differing from TTATC by a single A·T → G·C transition in the central triplet were cleaved at significantly reduced rates relative to TTATC, the order of preference being TAT > TGT > TAC > CAT. The guanine 2-amino group at positions 1 and 2, but not position 3, of a 5'-PyPuPy-3' trimer is implicated as a strong inhibitor of DNA binding by the copper-phenanthroline complex. The influence of the guanine 2-amino group and other features of the cleavage at PyPuPy triplets can be rationalized by a partial intercalation binding model in which one phenanthroline ring system intercalates into the DNA minor groove at the 5'-PyPu-3' step