Mechanisms of Mutagenic DNA Nucleobase Damages and Their Chemical and Enzymatic Repairs Investigated by Quantum Chemical Methods

Abstract

Selected Topics in DNA Repair 390 systems or reactions that may be too challenging or even impossible to study using such experimental techniques. Furthermore, it is nowadays possible to apply highly accurate and reliable computational methods to larger, more complete biochemical models. Thus, using such approaches one can not only reconcile theory with experiment but, for example, compare the feasibility of differing propose d r e a c t i o n m e c h a n i s m s o r i d e n t i f y n e w pathways. There have been numerous computational investigations on or related to DNA damage and repair. In this chapter the application of Computational Chemistry to the study of DNA damage and repair is illustrated through a review of a number of relevant computational investigations that we have performed. More specifically, we have applied high accuracy density functional theory (DFT)-based methods to the study of several important primary and secondary nucleobase damage pathways and repair mechanisms. The chapter is divided into sections, each of which focuses on select results concerning a damage and/or repair process involving either the nucleobase or phosphate components of DNA: 2. Nucleobase oxidation via ionizing radiation: describes primary redox damage in nucleobases. In particular, the Gibbs Free Energies of solution-phase electron (ET), proton (PT) and proton-coupled electron (PTET) transfers for all DNA bases are examined. In addition, the potential of alkylthiols to act as repair agents of such damage is considered. 3. 8-Oxopurine formation in purine, adenine and guanine: focuses on secondary damage of purine nucleobases. Specifically, the mechanisms of • OH attack leading to formation of 8-oxopurine derivatives are discussed as well as the Gibbs Free Energy changes of possible associated ET, PT and PTET processes. 4. Deamination of oxidized cytosine: examines the thermochemistry of several possible mechanisms by which oxidized cytosine, a pyrimidine nucleobase, may undergo deamination. 5. Oxidation of serine phosphate: Implications for DNA: investigates radicals formed from radiation-induced damage of serine phosphate. 6. Oxidative repair of alkylated nucleobases: The catalytic mechanism of AlkB: describes key results of our studies on the enzymatic mechanism of AlkB, a member of the family of α-ketoglutarate-Fe(II)-dependent dioxygenase enzymes that catalyse the oxidative repair of alkylated nucleobases.

A Density Functional Theory Investigation into the Binding of the Antioxidants Ergothioneine and Ovothiol to Copper.

“…2−5 For example, their action upon DNA is known to lead to a range of alterations including nucleobase and sugar modifications, phosphodiester backbone cleavage, and base-pair mismatching. 1 Such stress has been linked to aging and a variety of pathological disorders including cancer, Alzheimer's and Parkinson's disease. 6−10 In response, cells have developed a range of approaches to repair or mediate against such damages.…”

“…Reactive oxygen (ROS) and nitrogen (RNS) species are produced within cells, for instance, on exposure to ionizing radiation, as metabolic byproducts, or the action of free metal ions (e.g., Fe(II), Cu(I)) . Their generation can cause oxidative and nitrosative stress of important biomolecules including nucleic acids, proteins and lipids, resulting in their damage, malfunctioning or degradation. − For example, their action upon DNA is known to lead to a range of alterations including nucleobase and sugar modifications, phosphodiester backbone cleavage, and base-pair mismatching . Such stress has been linked to aging and a variety of pathological disorders including cancer, Alzheimer’s and Parkinson’s disease. − …”