DNA Damage and Disease

Evans M D, Dizdaroglu M, Cooke M S (2004). Oxidative DNA damage and disease induction, repair and significance. Mutation Res. 567 1-61. 

Bashir, S., Harris, G., Denman, A.M., Blake, D.R. and Win-yard, P.G. (1993). Oxidative DNA damage and cellular sensitivity to oxidative stress in human autoimmune disease. Ann. Rheum. Dis. 52, 659-666. 

The ATM protein has been identified as an important member of a reaction chain that leads from detection of DNA damage to activation of the p53 protein. Mutations of the ATM protein are causally associated with the disease ataxia telangiectasia, thus the name ATM (ataxia telangiectasia mutated). The ATM protein has protein kinase activity and is counted as a member of the PI3-kinase family, due to sequence homologies (review Canman et al., 1998). The p53 protein is phosphorylated at Serl5 by ATM kinase (Canman et al., 1998) and it is assumed that this phosphorylation contributes to activation of the p53 protein. The ATM protein is preceded by other protein kinases that are directly or indirectly activated by DNA damage and pass this signal on to the p53 protein via the ATM protein. 

Vitamins and minerals, whose main dietary sources are other than fruits and vegetables, are also likely to play a significant role in the prevention and repair of DNA damage, and thus are important to the maintenance of long-term health. Vitamin B12 is found in animal products, and deficiencies of B12 cause a functional folate deficiency, accumulation of the amino acid homocysteine (a risk factor for heart disease),46 and chromosome breaks. B12 supplementation above the RDA was necessary to minimize chromosome breakage.47 Strict vegetarians are at increased risk for developing vitamin B12 deficiency. 

Marijuana smokers are at higher risk than nonusers for chronic lung diseases such as bronchitis, asthma, lung infections, and emphysema. Research also indicates that heavy marijuana use can lead to the DNA damage and cellular changes that produce lung cancer these changes appeared to occur in marijuana smokers at an... 

There is considerable debate concerning the role played by free radical reactions, protein oxidation, DNA damage and lipid peroxidation in human disease and toxicology. Radical species have indeed been implicated in many disease states (Table 2.1). The question as to whether free radicals are a major cause of tissue damage in human disease or an accompaniment to or a consequence of such injury is by no means clear in many instances. However, what is clear is that diseased or damaged tissues undergo radical reactions more readily than normal, which may exacerbate the primary lesion. 

Epidemiological studies suggest that niacin may be implicated in the pathogenesis of Parkinson s disease via the following process. NAD produced from niacin releases nicotinamide via poly(ADP-ribosyl)ation which is activated in Parkinson s disease. Released excess nicotinamide is methylated to 1-methylnicotinamide (MNA) in the cytoplasm by nicotinamide N-methyltransferase. MNA destroys several subunits of complex I via superoxide formation. This can destroy complex I subunits either directly or indirectly via mitochondrial DNA damage, and stimulates poly(ADP-ribosyl)ation. It has been proposed that this implicates nicotinamide as a potential causal agent in the development of Parkinson s disease (Fukushima et al., 2004). 

Finally, the linear low-dose extrapolation obviates de facto the concept of a threshold in the dose-response curve. The threshold concept is universally accepted for most other, noncancer toxicity and for many other biological phenomena (e.g., taste thresholds), and many scientists would argue that such thresholds (or practical thresholds ) should apply to the cancer or mutation response due to the undo-lying complexities in toxicokinetics and in the dynamics of DNA damage and repair, immune surveillance, and the variation in the progression of clinical diseases. ... 

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. 

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