Background Levels of DNA Damage in the Population

Saul, Robert L.; Ames, Bruce N.

doi:10.1007/978-1-4615-9462-8_55

Mechanisms of DNA Damage and Repair 1986

DOI: 10.1007/978-1-4615-9462-8_55

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Background Levels of DNA Damage in the Population

Robert L. Saul

Bruce N. Ames

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1987

2011

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Cited by 60 publications

(37 citation statements)

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“…1). It is estimated that 400 Tgs are formed per cell per day (1,2), and the presence of Tg in DNA has been used as a marker for oxidative stress (1,3). Moreover, Tg is one of the predominant types of base modifications produced by ionizing radiation (4,5), including that used in cancer therapy.…”

mentioning

confidence: 99%

A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol

Aller

Rould

Hogg³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

133

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Thymine glycol (Tg) is a common product of oxidation and ionizing radiation, including that used for cancer treatment. Although Tg is a poor mutagenic lesion, it has been shown to present a strong block to both repair and replicative DNA polymerases. The 2.65-Å crystal structure of a binary complex of the replicative RB69 DNA polymerase with DNA shows that the templating Tg is intrahelical and forms a regular Watson-Crick base pair with the incorporated A. The C5 methyl group protrudes axially from the ring of the damaged pyrimidine and hinders stacking of the adjacent 5 template guanine. The position of the displaced 5 template guanine is such that the next incoming nucleotide cannot be incorporated into the growing primer strand, and it explains why primer extension past the lesion is prohibited even though DNA polymerases can readily incorporate an A across from the Tg lesion.oxidative DNA damage ͉ structure ͉ DNA replication T hymine glycol (5,6-dihydro-5,6-dihydroxythymine; Tg), the most common oxidation product of thymine, is produced endogenously as a consequence of aerobic metabolism or via exogenous factors such as chemical oxidants or ionizing radiation (Fig. 1). It is estimated that 400 Tgs are formed per cell per day (1, 2), and the presence of Tg in DNA has been used as a marker for oxidative stress (1, 3). Moreover, Tg is one of the predominant types of base modifications produced by ionizing radiation (4, 5), including that used in cancer therapy.Of the oxidatively modified DNA bases retaining an intact ring, Tg is thought to induce the most distortion in the regular structure of DNA. Even though there are DNA repair enzymes specialized in excising Tg from the genome, such as human , statistically a few of the damaged bases will evade repair, which means that DNA polymerases will encounter these lesions during replication. Although Tg is a poor mutagenic lesion because it generally pairs with A (9), it has been shown to be a very effective block to DNA replication (10-13). When Tg is encountered as a templating base by replicative or repair polymerases, termination of primer extension occurs immediately past the lesion site with A inserted opposite the Tg. Even in the presence of proofreading, extension proceeds no further. This finding contrasts with the situation observed when the lesion is an abasic site, where, in the presence of proofreading, termination sites are observed one base before the lesion (14). Therefore, it is extension past the Tg⅐adenine pair, rather than insertion across Tg, that constitutes the block to the replicative polymerases. Because Tg is a strong block to repair and replicative DNA polymerases in vitro (10-13), not surprisingly, it is a lethal lesion in vivo (9,(15)(16)(17)(18).Unlike normal DNA bases, Tg is nonplanar because of the loss of aromatic character that accompanies the addition of hydroxyl groups at the 5 and 6 positions of the ring (19). Computational simulations (20,21) predict that the axial orientation of the methyl group with respect to the pyrimidine r...

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mentioning

confidence: 99%

A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol

Aller

Rould

Hogg³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

133

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“…Although cells have developed various enzymatic and nonenzymatic systems to control excited oxygen species (2), a certain fraction escapes the cellular defense and may cause permanent or transient damage to proteins, lipids, and nucleic acids. Oxidative damage has been suggested to contribute to aging and to a host of diseases including cancer, chronic inflammation, ischemia, degenerative arterial, and autoimmune diseases (3)(4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

“…Since DNA plays a central role in the information transfer between generations of somatic cells, much attention has been given to its oxidative damage, particularly in relation to aging and cancer (3,(5)(6)(7)(8)(9)(10)(11)(12). A high rate of oxidative damage to mammalian DNA has been demonstrated by measuring oxidized DNA bases excreted in urine after DNA repair (5)(6)(7)(8). The rate of oxidative DNA damage is directly related to the metabolic rate and inversely related to life span ofthe organisms (7).…”

mentioning

confidence: 99%

Normal oxidative damage to mitochondrial and nuclear DNA is extensive.

Richter

Park

Ames

1988

Proc. Natl. Acad. Sci. U.S.A.

1,516

817

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Oxidative damage to DNA can be caused by excited oxygen species, which are produced by radiation or are by-products of aerobic metabolism. The oxidized base, 8-hydroxydeoxyguanosine (oh8dG), 1 of =20 known radiation damage products, has been assayed in the DNA of rat liver. oh'dG is present at a level of 1 per 130,000 bases in nuclear DNA and 1 per 8000 bases in mtDNA. Mitochondria treated with various prooxidants have an increased level of oh8dG. The high level of oh8dG in mtDNA may be caused by the immense oxygen metabolism, relatively inefficient DNA repair, and the absence of histones in mitochondria. It may be responsible for the observed high mutation rate of mtDNA.

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“…Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants). Four endogenous processes leading to significant DNA damage are oxidation (1-3), methylation, deamination, and depurination (2). The importance of these processes is supported by the existence of specific DNA repair glycosylases for oxidative, methylated, and deaminated adducts and a repair system for apurinic sites that are produced by spontaneous depurination (3).…”

mentioning

confidence: 99%

DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis.

Ames

Shigenaga

Gold

1993

Environ Health Perspect

268

155

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DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 106 oxidative lesions are present per rat cell. An exogenous mutagen produces an increment in lesions over the background rate of endogenous lesions. The effectiveness of a particular lesion depends on whether it is excised by a DNA repair system and the probability that it gives rise to a mutation when the cell divides. When the cell divides, an unrepaired DNA lesion has a certain probability of giving rise to a mutation. Thus, an important factor in the mutagenic effect of an exogenous agent whether it is genotoxic or non-genotoxic, is the increment it causes over the background cell division rate (mitogenesis) in cells that appear to matter most in cancer, the stem cells, which are not on their way to being discarded. Increasing their cell division rate increases mutation and therefore cancer. There is little cancer from nondividing cells. Endogenous cell division rates can be influenced by hormone levels, decreased by calorie restriction, or increased by high doses of chemicals. If both the rate of DNA lesions and cell division are increased, then there will be a multiplicative effect on mutagenesis (and carcinogenesis), for example, by high doses of a mutagen that also increases mitogenesis through cell killing. The defense system against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible and buffer cells against increments in active forms of chemicals that can cause DNA lesions. A variety of DNA repair defense systems, almost all inducible, buffer the cell against any increment in DNA lesions. Therefore, the effect of a particular chemical insult depends on the level of each defense, which in turn depends on the past history of exposure. Exogenous agents can influence the induction and effectiveness of these defenses. Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants). Four endogenous processes leading to significant DNA damage are oxidation (1-3), methylation, deamination, and depurination (2). The importance of these processes is supported by the existence of specific DNA repair glycosylases for oxidative, methylated, and deaminated adducts and a repair system for apurinic sites that are produced by spontaneous depurination (3). Endogenous DNA Damage and MutagenesisDNA damage produced by oxidation appears to be the most significant endogenous damage (4). We estimate that the DNA hits per cell per day from endogenous oxidants are normally 105 in the rat and 104 in the human (5-7). These oxidative lesions are effectively but not perfectly repaired; the normal steady-state level of oxidative DNA lesions is about 106 per cell in the young rat and about twice this in the old rat (6,8). Oxidants are produced as byproducts of mitochondrial electron transport, various oxygen-utilizing enzyme system, peroxisomes, and other processes associated with normal aerobic metabolism...

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Background Levels of DNA Damage in the Population

Cited by 60 publications

References 20 publications

A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol

A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol

Normal oxidative damage to mitochondrial and nuclear DNA is extensive.

DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis.

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