**10. DNA repair: Introduction**

To maintain the genomes of organisms, they have evolved a network of DNA repair pathways to excise altered residues from DNA. A major consideration is the relative contribution of environmental and endogenous DNA damage to carcinogenesis. DNA damage by environmental agents would have to be extensive and exceed that produced by normal endogenous reactive chemicals to be a major contributor to mutations and cancer. This consideration underlines the difficulty in extrapolating risk of exposure to that which would occur at very low doses of carcinogens

### **10.1 DNA repair and role of micronutrients as biomarkers of susceptibility to DNA damage**

Very many factors including nutritional factors have been shown to delay the carcinogenic process. Thus this can be exploited to reverse, delay or prevent the carcinogenic process. Maintenance of genome stability is of fundamental importance for counteracting carcinogenesis. Many human genome instability syndromes exhibit a predisposition to cancer. An increasing body of epidemiological evidence has suggested a link between nutrient status and risk of cancer. Populations in developing countries that are deficient in these protective micronutrients (WHO, 2002; Ames, 2010) and are increasingly exposed to chemicals owing to progressive or rapid industrialization are thus at increased risk (Anetor et al., 2008). Based on public data from the healthy people 2010 project, it is estimated that up to 80% of colon and prostate cancers may be influenced by diet, nutrition and life styles. As earlier indicated, it has been proposed that DNA damage induced by dietary micronutrient deficiency accounts for one-third of preventable cancers. Because micronutrient deficiencies can induce DNA damage in forms similar to those induced by ionizing radiation and reactive oxygen species (ROS), it has been suggested that oxidative stress and associated DNA breaks are critical targets for nutritional control of carcinogenesis. If left unrepaired, DNA lesions can promote accumulation of mutations that facilitate the process of carcinogenesis.

Micronutrients may act directly on the genome to prevent mutations, or indirectly as enzyme cofactors in cellular processes that modulate transformation. Thus micronutrient status may serve as biomarkers of risk of carcinogenesis. For instance low selenium status is a biomarker of risk of many cancers including cancer of the prostate. This should be particularly appealing to industrializing developing countries. Human cells possess an armamentarium of mechanisms for DNA repair that counter the extensiveness of DNA damage caused both by endogenous and environmental chemicals. These mechanisms include base excision repair (BER) that removes products of alkylation and oxidation (Duncan et al, 1976; Roth and Samson, 2002; Gersson, 2002); nucleotide excision repair (NER) that excises oligonucleotide segments containing larger adducts (Setlow and Carrier, 1963); mismatch repair that scans DNA immediately after polymerization for misincorporation by DNA polymerases (Modrich, 1991); and oxidative demethylation (Sedgwick, 2004), transcription-coupled repair (TCR) that preferentially repairs lesions that block transcription ( Hanawalt, 1994); double-strand break repair and recombination that avoids errors by copying the opposite DNA strand (Friedberg et al, 2005); as well as mechanisms for the repair of cross-links between strands ( Kuraoka et al, 2000; Zheng et al, 2005) that yet need to be established. Micronutrients deficiency disorder may inhibit DNA repair, thus acting as risk factors. Determinations of the levels of micronutrients may therefore serve as biomarker of susceptibility to DNA damage using the various instruments provided by biomedical engineering. Micronutrient deficiency for instance is inversely correlated with the level of 8-hydrodeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, which is mutagenic and has to be removed by protective enzymes such as the human oxo-guanine DNA glycosylase (hOGG1).

Most DNA lesions are subject to repair by more than one pathway. As a result, only a minute fraction of DNA lesions which escapes correction are present at the time of DNA

This consideration underlines the difficulty in extrapolating risk of exposure to that which

Very many factors including nutritional factors have been shown to delay the carcinogenic process. Thus this can be exploited to reverse, delay or prevent the carcinogenic process. Maintenance of genome stability is of fundamental importance for counteracting carcinogenesis. Many human genome instability syndromes exhibit a predisposition to cancer. An increasing body of epidemiological evidence has suggested a link between nutrient status and risk of cancer. Populations in developing countries that are deficient in these protective micronutrients (WHO, 2002; Ames, 2010) and are increasingly exposed to chemicals owing to progressive or rapid industrialization are thus at increased risk (Anetor et al., 2008). Based on public data from the healthy people 2010 project, it is estimated that up to 80% of colon and prostate cancers may be influenced by diet, nutrition and life styles. As earlier indicated, it has been proposed that DNA damage induced by dietary micronutrient deficiency accounts for one-third of preventable cancers. Because micronutrient deficiencies can induce DNA damage in forms similar to those induced by ionizing radiation and reactive oxygen species (ROS), it has been suggested that oxidative stress and associated DNA breaks are critical targets for nutritional control of carcinogenesis. If left unrepaired, DNA lesions can promote accumulation of mutations that

Micronutrients may act directly on the genome to prevent mutations, or indirectly as enzyme cofactors in cellular processes that modulate transformation. Thus micronutrient status may serve as biomarkers of risk of carcinogenesis. For instance low selenium status is a biomarker of risk of many cancers including cancer of the prostate. This should be particularly appealing to industrializing developing countries. Human cells possess an armamentarium of mechanisms for DNA repair that counter the extensiveness of DNA damage caused both by endogenous and environmental chemicals. These mechanisms include base excision repair (BER) that removes products of alkylation and oxidation (Duncan et al, 1976; Roth and Samson, 2002; Gersson, 2002); nucleotide excision repair (NER) that excises oligonucleotide segments containing larger adducts (Setlow and Carrier, 1963); mismatch repair that scans DNA immediately after polymerization for misincorporation by DNA polymerases (Modrich, 1991); and oxidative demethylation (Sedgwick, 2004), transcription-coupled repair (TCR) that preferentially repairs lesions that block transcription ( Hanawalt, 1994); double-strand break repair and recombination that avoids errors by copying the opposite DNA strand (Friedberg et al, 2005); as well as mechanisms for the repair of cross-links between strands ( Kuraoka et al, 2000; Zheng et al, 2005) that yet need to be established. Micronutrients deficiency disorder may inhibit DNA repair, thus acting as risk factors. Determinations of the levels of micronutrients may therefore serve as biomarker of susceptibility to DNA damage using the various instruments provided by biomedical engineering. Micronutrient deficiency for instance is inversely correlated with the level of 8-hydrodeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, which is mutagenic and has to be removed by protective enzymes such as the

Most DNA lesions are subject to repair by more than one pathway. As a result, only a minute fraction of DNA lesions which escapes correction are present at the time of DNA

**10.1 DNA repair and role of micronutrients as biomarkers of susceptibility to DNA** 

would occur at very low doses of carcinogens

facilitate the process of carcinogenesis.

human oxo-guanine DNA glycosylase (hOGG1).

**damage** 

replication and can direct the incorporation of noncomplementary nucleotides resulting in mutation. Unrepaired DNA lesions initiate mutagenesis by stalling DNA replication forks or are copied over by error-prone *trans*-lesion DNA polymerases (McCulloch and Kunkel, 2008). Alternatively, incomplete DNA repair can result in the accumulation of mutations and mutagenic lesions, such as abasic sites (Loeb, 1985). Maintenance of genome stability is crucial for avoiding carcinogenesis. A number of human cancers display a range of chromosomal abnormalities; a characteristic now termed genome instability. The relationship between cancer and genome instability is well recognized, but the causes of genome instability in the evolution of human cancers is incompletely elucidated. The DNA damage response safeguards the integrity of the genome by detecting alterations, halting cell cycle progression and repairing damaged DNA. Zinc which plays a role in all the phases of cell cycle when deficient can be critical. (Anetor et al, 2008) Cells with defective DNA damage responses are characterized by high level of genome instability (Cheng, 2009).

It is known that in particular, cells in s-phase are vulnerable to agents, such as chemicals in the environment that cause DNA damage and induce DNA replication fork arrest. Since such events can adversely affect genomic stability, cells have evolved S-phase DNA response cascades, including checkpoint responses and DNA repair mechanisms, to fix DNA damage (Bartek et al., 2004). In response to DNA damage, check points are activated that coordinate DNA damage signaling, cell cycle arrest and DNA repair. Cells have developed elaborate systems to repair varieties of DNA damage. Abundant evidence has linked defects in DNA repair to carcinogenesis. As a way of avoiding mutagenic events, the DNA base excision repair (BER) pathway copes with oxidatively modified DNA (Xu et al., 1997; Kungland et al., 1999), and nucleotide excision repair can deal with bulky DNA adducts including DNA cross-links (Cleaver, 2005). It is noteworthy that micronutrient deficiency significantly affects DNA damage repair. Zinc (Zn) deficiency is common in children and adults (WHO, 2002; Moshfegh et al., 2005). Human cell culture studies demonstrating severe Zn deficiency causes complex IV deficiency and the release of oxidants, resulting in significant oxidative DNA damage (Ho and Ames, 2002). Zinc deficiency has also been reported to cause chromosome breaks in rats (Bell et al, 1975) which has been associated with cancer in both animal models and humans (Fong et al., 2005).

These reports strengthen the significant effect of micronutrient deficiency on DNA damage repair and by extrapolation on risk of carcinogenesis particularly chemical carcinogenesis in populations exposed to chemicals. Zinc deficiency in human cells has also been shown to inactivate Zn-containing proteins such as the tumor suppressor protein, p53 which plays a significant role in genome protection (Lane, 1992) and the DNA base excision repair enzyme,apyrimidinic/apurinic endonuclease, with a resulting synergistic effect on genetic damage (Ho and Ames, 2002;Ho Courtemanche and Ames, 2003).

### **11. Integrative cell biology and chemical carcinogenesis**

Damage to DNA by chemical carcinogens activates checkpoint signaling pathways leading to cell cycle arrest and allows time for DNA repair processes (Sweasy et al, 2006). In the absence of repair, cells can use special DNA polymerases that copy past DNA adducts (Masutani et al., 2000) or undergo apoptosis by signaling the recruitment of immunologic and inflammatory host defense mechanisms. The demonstration that each methylcholanthrene-induced tumor has a unique antigenic signature provided one of the earliest glimpses into the stochastic nature of cellular responses to carcinogens. The immunologic and inflammatory responses facilitate not only engulfment and clearance of damaged cells but also the resulting generation of reactive oxygen (Klebanoff, 1988) and nitrogen radicals (Ohshima and Batsch, 1994) that further damage cellular DNA.
