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

Abstract

A cells genetic information, its 'blueprint of life', is contained within its DNA. This biologically important molecule, however, can be attacked by high–energy ionizing radiation and oxidizing agents resulting in a range of possible damage. For instance, nucleobases can undergo chemical modifications or degradation such as oxidation, deamination, alkylation or be cleaved from the sugar-phosphate backbone. (De Bont & van Larebeke 2004; Friedberg et al. 2004; Hecht 1999; Kamiya et al. 1998; Labet et al. 2008a; Lindahl 1993; Lysetska et al. 2002; Neeley & Essigmann 2006; Rydberg & Lindahl 1982; Taylor 1994; Wang 2008) Similarly, the deoxyribose sugar moieties may also undergo various chemical modifications. These events can lead further to the formation of DNA– DNA or DNA–protein cross–links or DNA–strand breaks. (Kumar & Sevilla 2010; Lipfert et al. 2004) Importantly, damage to DNA can significantly affect its replication and transcription. This can ultimately result in cell apoptosis or protein mutations and pathological diseases such as cancer. (Pages & Fuchs 2002) Experimentally, there have been numerous detailed in vivo and in vitro investigations into the processes and pathways involved in the damage of DNA. (See, for instance, Kumar & Sevilla 2010; Mishina et al. 2006, Wetmore et al. 2001) Radiolysis experiments with photometric, electrochemical and electron paramagnetic resonance detection, enzymatic inhibition and mutagenesis studies have identified a large number of reaction intermediates and rate constants for many damage and repair processes. For more in-depth reviews of experimental investigations on DNA damage processes the reader is also directed to relevant chapters in this present book. Unfortunately, however, many uncertainties and questions still remain about DNA damage and repair. Computational chemistry provides an alternate and also complementary approach for obtaining a deeper understanding of chemical processes. This is in part because it can not only be applied to systems that are amenable to experimental investigation but also to those