The Chemical Biology of DNA Damage

Nicholas E. Geacintov, Suse Broyde, Nicholas E. Geacintov, Suse Broyde

• Publisher: Wiley-VCH
• Year: 2011
• Print ISBN: 9783527322954
• eBook ISBN: 9783527642113
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biochemistry
• Index: Biological Sciences

Bringing the power of biochemical analysis to toxicology, this modern reference explains genotoxicity at the molecular level, showing the links between a DNA lesion and the resulting cellular or organismic response. Clearly divided into two main sections, Part 1 focuses on selected examples of important DNA lesions and their biological impact, while the second part covers current advances in assessing and predicting the genotoxic effects of chemicals, taking into account the biological responses mediated by the DNA repair, replication and transcription machineries.
A ready reference for biochemists, toxicologists, molecular and cell biologists, and geneticists seeking a better understanding of the impact of chemicals on human health.

Part One

Chemistry and Biology of DNA Lesions

1

Introduction and Perspectives on the Chemistry and Biology of DNA Damage

Nicholas E. Geacintov and Suse Broyde

1.1 Overview of the Field

The subject of this book, the chemical biology of DNA damage, is concerned with the chemistry that produces DNA damage, and the relationships between the structural features of the DNA lesions formed and their biological impact. The subjects and examples described illustrate the interdisciplinary approaches that can be used to bridge the gaps between the chemical aspects and biological end-points of DNA damage, especially lesions generated by different endogenous and exogenous DNA-damaging agents. In Part One (Chapters 2–8), the focus is on the chemistry and biological impact of some representative and important DNA lesions. The topics of Part Two (Chapters 9–17) deal with recent and current research on the relationships between the chemical structure and physical properties of selected DNA lesions, and how the lesions are processed by the DNA repair, replication, and transcription machineries.

The chemistry of DNA damage is complex and the variety of DNA lesions is enormous. This book considers an important subset of DNA lesions that illustrate the relationships between the chemistry, structure, biochemistry, and biology of DNA damage. In this chapter, we provide a broad but brief overview of this vast field. Some of the established links between DNA damage and human diseases are highlighted. The objectives of this chapter are to situate the topics covered in this book within the overall field and to guide the interested reader to the original literature concerned with topics that either are or are not explicitly covered in the rest of the book.

We begin with an overview of the origins of DNA damage, followed by summaries of the relationships between DNA lesions and disease, and a brief overview of cellular DNA damage response (DDR) systems, and conclude with a brief description of the specific topics covered in this book and how they relate to the field overall.

1.2 DNA Damage–A Constant Threat

The human genome is under constant attack from endogenous and exogenous reactive chemical species. A variety of genotoxic agents can induce chemical transformation of the nucleotides or damage the phosphodiester backbone of DNA with deleterious consequences for the cell. The relationships between cellular DNA damage caused by endogenous and environmental genotoxic agents, the cellular response, and the development and prevention of human diseases and aging are areas of great current interest in the medical, biological, and chemical research communities [1].

It has been estimated that there are tens of thousands of DNA-damaging events per day suffered by the approximately 10¹³ cells within the human body [2] and that DNA damage associated with endogenous species is more extensive (greater than 75%) than damage caused by environmental factors [3]. Among the endogenous species that damage cellular DNA are reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive intermediates are produced under conditions of oxidative stress, a consequence of normal metabolic activity, and the inflammatory response [3, 4]. Other forms of endogenous DNA damage are depu-rination (and to a lesser extent depyrimidination) that arise from the hydrolysis of the glycosidic bonds between the nucleobase and deoxyribose residues, thus leading to the formation of apurinic (or apyrimidinic) sites [5]. The hydrolytic deamination of cytosine can also occur spontaneously and give rise to uracil [6]. Both forms of DNA damage, if not repaired by the normally efficient cellular base excision repair (BER) mechanism, can result in the mutagenic insertion of an incorrect base during error-prone translesion synthesis when the DNA is replicated past the lesion.

Among the external causes of DNA damage are ionizing radiation and solar UV radiation. Sunlight has been called the most prominent and ubiquitous physical carcinogen in our natural environment [7]. There are ample epidemiological data and a wealth of supporting animal model experiments that indicate that solar UV radiation is a major cause of skin cancer among the white Caucasian populations in the Western world [8]. The UV portion of the solar spectrum in the 290- to 300-nm region is absorbed by DNA and forms cyclobutane pyrimidine dimers (CPDs) that have been linked to the etiology of skin cancer [9]. Ionizing radiation is routinely used in medical diagnostic and chemotherapeutic applications. There are different forms of radiation that generate a variety of DNA lesions that include double- and single-strand breaks, as well as oxidatively modified nucleobases and deoxyribose moieties. The human population is also continuously exposed to environmental pollutants that are present in air, water, and food [10]. Many of these chemicals are metabolized in human cells to highly reactive intermediates that react chemically with the nucleobases to form deleterious DNA strand breaks and a variety of DNA lesions or adducts that are readily detectable in human cells [11–13]. Fortunately, nature has devised a host of cellular defense or DNA repair mechanisms that have been described [14] and reviewed in a comprehensive monograph [15]. Some of the mechanisms that involve the removal of DNA lesions are discussed in Chapters 11 and 12. The effects of DNA lesions that escape repair can be bypassed during DNA replication by a damage tolerance mechanism that depends on the actions of a set of specialized polymerases [16, 17] or through homologous recombination mechanisms that leave the lesion intact on the damaged strand [18].

1.3 DNA Damage and Disease

1.3.1 The Inflammatory Response

Chronic inflammation in mammalian tissues can be caused by a variety of chemical, physical, and infectious factors that are not only cytotoxic, but can also increase the risk of malignant cell transformation and promote the development of various human cancers [19]. The inflammatory response includes the activation of mac-rophage and neutrophil cells that result in a complex spectrum of chemically reactive species that damage DNA and other biomolecules [4]. Activated macro-phages overproduce nitric oxide (NO) and superoxide (

) that combine rapidly to form peroxynitrite (ONOO⁻ ). The latter decomposes to reactive intermediates that can cause damage to DNA and other biomolecules (see Chapters 2–4). The activated neutrophils, on the other hand, contribute to the myeloperoxidase-medi-ated generation of hypochlorous acid (HOCl) –a potent oxidizing and halogenating agent [4]. While many of the DNA lesions formed are oxidized forms of DNA bases themselves [20, 21], more bulky DNA lesions can also arise from the endogenous peroxidation of lipids that generate highly reactive aldehyde derivatives that react with DNA [22] (see also Chapters 5 and 9). The generation of guanine radical intermediates also leads to the formation of cross-linking reactions with thymine [20, 23] as discussed in Chapters 3 and 4.

1.3.2 Reactive Oxygen and Nitrogen Species

DNA lesions caused by reactions with ROS and RNS that are byproducts of the inflammatory response have also been implicated in the etiology of neurological diseases such as Alzheimer’s [24] and Parkinson’s [25]. Furthermore, oxidatively generated DNA damage has been implicated in aging, based on the hypothesis that DNA damage accumulation contributes to this natural phenomenon [26–28]. The elevated concentrations of ROS and RNS alter the intracellular signaling pathways via inflammatory cytokines; this can result in an imbalance between oxidative damage of cellular DNA and DNA repair processes, causing the accumulation of DNA lesions in the genome. If not removed by cellular DNA repair mechanisms, the cytotoxic lesions may result in abnormal cell physiology, apoptosis, and cell death if DNA replication or transcription is inhibited, or may cause mutations and cancer if error-prone translesion bypass occurs.

1.3.3 Early Recognition of Environmentally Related Cancers: Polycyclic Aromatic Hydrocarbons

The connections between environmental chemicals and cancer have a long history [29], dating to the eighteenth century when the first correlation was made between exposure to soot and the high incidence of scrotal cancer among chimney sweeps in London. During the twentieth century, a combination of epidemiological and animal experiments has provided persuasive evidence that polycyclic aromatic hydrocarbons (PAHs), such as the well-known and representative compound benzo[a]pyrene (B[a]P), are key chemical carcinogens in soot and coal tar. While PAH compounds are chemically unreactive and are, at best, sparingly soluble in aqueous solutions, a seminal early observation documented that these and other bulky aromatic compounds are metabolically activated by microsomal P450 enzymes to oxygenated derivatives with higher water solubilities, thus facilitating their excretion [30]. Among these metabolites, however, are highly reactive elec-trophiles that can react chemically with nucleic acids to form covalent DNA adducts (Chapter 6). The link between DNA damage and cancer risk is difficult to establish in humans. However, decades of epidemiological evidence and studies of animal chemical carcinogenesis models point to DNA adducts as being of central importan...

Table of contents

• Cover
• Title
• Further Reading
• Copyright
• Preface
• List of Contributors
• Part One: Chemistry and Biology of DNA Lesions
• Part Two: New Frontiers and Challenges: Understanding Structure— Function Relationships and Biological Activity
• Index