DNA-DITERCALINIUM INTERACTIONS - IMPLICATIONS FOR RECOGNITION OF DAMAGED DNA

Ditercalinium is unique among known DNA-binding chemotherapeutic agents. Ditercalinium treatment of Escherichia coli causes cell death by provoking malfunction of the (A)BC exinuclease excision DNA repair system. In this report, we describe the three-dimensional X-ray structure of a ditercalinium-[d(CGCG)]2 complex in detail with an analysis of both the structure and its implications. Ditercalinium bisintercalates in the DNA fragment; the positively-charged linker of the drug interacts with the major groove. The DNA retains an underwound, right-handed, double-helical conformation with a bend of around 15-degrees in the helical axis. One striking feature of the complex is the extensive interaction of ditercalinium with guanines in contrast to the near absence of interaction with cytosines. The terminal cytosines in particular are "unstacked" from the rest of the complex. A systematic comparison of the three-dimensional structure of the DNA-ditercalinium complex with those of triostin A and nogalamycin (chemotherapeutic agents that act by conventional mechanisms) allows us to suggest a general model for recognition by the (A)BC exinuclease excision repair system. It is commonly hypothesized that the same distorted conformation of DNA results from modification by each member of a diverse family of DNA-damaging agents. This specific conformation of DNA would then be recognized by the (A)BC exinuclease excision repair system. Alternatively, we propose that each of these damaging agents causes local instability of DNA (but not necessarily a common conformation) and that the (A)BC exinuclease excision repair system recognizes excessive or unusual deformability of damaged DNA in comparison to normal DNA.