Looking beneath the surface to determine what makes DNA damage deleterious

Abstract

Apurinic/apyrimidinic and oxidized abasic sites are chemically reactive DNA lesions that are produced by a variety of damaging agents. The effects of these molecules that lack a Watson-Crick base on polymerase enzymes are well documented. More recently, multiple consequences of the electrophilic nature of abasic lesions have been revealed. Members of this family of DNA lesions have been shown to inactivate repair enzymes and undergo spontaneous transformation into more deleterious forms of damage. Abasic site reactivity provides insight into the chemical basis for the cytotoxicity of DNA damaging agents that produce them and are valuable examples of how looking beneath the surface of seemingly simple molecules can reveal biologically relevant chemical complexity.

Figure 1

DNA damage. A. There is an inverse relationship between the biological hierarchy of DNA damage and their formation frequency. (X = DNA lesion) B. Representative electrophilic DNA lesions.

Figure 2

DNA interstrand cross-link formation. A. Trapping of an ICL between AP and dG under reductive conditions. B. ICL formation from C4-AP.

Figure 3

Base excision repair. A. Series of enzyme reactions starting from excision of a damaged nucleotide (X) by a glycosylase. B. Incision of an AP site by Ape1, followed by removal of dRP by Pol β via Schiff-base formation. C. 2-Deoxyribonolactone (L) inactivation of Nth, a bifunctional glycosylase. D. Pol β inactivation by DOB. E. Pol β inactivation by incised C4-AP (pC4-AP).

Figure 4

DNA lesion reactivity in nucleosome core particles (NCPs). A. X-ray crystal structure of a single-gyre of the NCP composed of α-satellite DNA (PDB: 1aoi). The numbers 0–7 indicate superhelical locations (SHL). B. AP reactivity in a NCP.