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.

Rapid Histone-Catalyzed DNA Lesion Excision and Accompanying Protein Modification in Nucleosomes and Nucleosome Core Particles

“…2–7 Elucidating the biochemical consequences of these lesions provides insight into the chemical basis for the cytotoxicity of the agents that produce them. 8,9 For instance, AP, C4-AP, and L are highly mutagenic, and more recently interesting aspects of their chemical reactivity have been uncovered. 10–14 For example, AP, C4-AP, and DOB yield DNA interstrand cross-links.…”

A ROS‐Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds

“…In principle, the formation of a single or few alterations or inhibitory events within the three billion base pair genome can be sufficient to cause cancer cell apoptosis due to lack of repair, which represents a reaction yield of 10 −8 . [3, 4] Recently, the development of DNA-altering agents has been extended to conjugation with cell-targeting antibodies, as in the case of the CD33-targeted antibody in gemtuzumab ozogamicin. [5] We used an alternative and complementary approach based on selective activation by reactive oxygen species (ROS) to design next-generation smart DNA modifiers, termed ROS-activated cytotoxic agents (RACs).…”

Trinucleotide Repeat Instability is Modulated by DNA Base Lesions and DNA Base Excision Repair

“…In addition, some types of oxidized lesions such as the C4-oxidized AP site (C4-AP) and 5'-(2-phosphoryl-1,4-dioxobutane) (DOB) can irreversibly inhibit the BER protein DNA polymerase β (pol β) by forming a covalent crosslink with a key lysine residue in the active site of the deoxyribose phosphate (dRP) lyase domain (38), thus preventing efficient repair.…”

“…During repair of an oxidized DOB lesion, the dRP lyase domain of pol  has been found to form a covalent crosslink with the DOB lesion (38,247,249,250). Whether this crosslink can still form when the DOB lesion occurs in the loop of a hairpin resulting in lesion formation at the end of a 5'-flap has yet to be explored.…”

“…These sugar modifications are compared in Figure 3.1. DOB forms a permanent covalent crosslink with Lys72 (and Lys84 to a lesser extent) in the dRP lyase domain of pol β (247), which is responsible for Schiff base formation during the β elimination reaction (248), resulting in a DNA-protein crosslink, irreversible inhibition of pol β dRP lyase following ~ 4 turnovers of the enzyme, and a decrease in pol β DNA synthesis activity (38,247,249,250). Here we explore the effects of sugar modification on the activity of BER proteins during repair in a TNR tract and the downstream effects of crosslink formation on BER efficiency.…”