Oxidatively induced DNA damage: Mechanisms, repair and disease

Biochemical Science Division, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA. Electronic address: .
Cancer letters (Impact Factor: 5.62). 01/2012; 327(1-2):26-47. DOI: 10.1016/j.canlet.2012.01.016
Source: PubMed


Endogenous and exogenous sources cause oxidatively induced DNA damage in living organisms by a variety of mechanisms. The resulting DNA lesions are mutagenic and, unless repaired, lead to a variety of mutations and consequently to genetic instability, which is a hallmark of cancer. Oxidatively induced DNA damage is repaired in living cells by different pathways that involve a large number of proteins. Unrepaired and accumulated DNA lesions may lead to disease processes including carcinogenesis. Mutations also occur in DNA repair genes, destabilizing the DNA repair system. A majority of cancer cell lines have somatic mutations in their DNA repair genes. In addition, polymorphisms in these genes constitute a risk factor for cancer. In general, defects in DNA repair are associated with cancer. Numerous DNA repair enzymes exist that possess different, but sometimes overlapping substrate specificities for removal of oxidatively induced DNA lesions. In addition to the role of DNA repair in carcinogenesis, recent evidence suggests that some types of tumors possess increased DNA repair capacity that may lead to therapy resistance. DNA repair pathways are drug targets to develop DNA repair inhibitors to increase the efficacy of cancer therapy. Oxidatively induced DNA lesions and DNA repair proteins may serve as potential biomarkers for early detection, cancer risk assessment, prognosis and for monitoring therapy. Taken together, a large body of accumulated evidence suggests that oxidatively induced DNA damage and its repair are important factors in the development of human cancers. Thus this field deserves more research to contribute to the development of cancer biomarkers, DNA repair inhibitors and treatment approaches to better understand and fight cancer.

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Available from: Miral Dizdaroglu, Dec 10, 2015
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    • "Oxidized DNA base lesions induced by environmental pollutants and endogenous metabolites lead to a variety of mutations and consequently to genetic instability, which is a hallmark of cancer [1] [2]. As shown in European populations , increased frequencies of chromosome aberrations and micronuclei are closely associated with cancer risk [3] [4]. "
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    ABSTRACT: Genome instability and impaired DNA repair are hallmarks of carcinogenesis. The study was aimed at evaluating the DNA damage response in H 2 O 2 -treated lymphocytes using the alkaline comet assay in bladder cancer (BC) patients as compared to clinically healthy controls, elderly persons, and individuals with chronic inflammations. Polymorphism in DNA repair genes involved in nucleotide excision repair (NER) and base excision repair (BER) was studied using the PCR-RFLP method in the Belarusian population to elucidate the possible association of their variations with both bladder cancer risk and clinicopathological features of tumors. The increased level of H 2 O 2 -induced DNA damage and a higher proportion of individuals sensitive to oxidative stress were found among BC patients as compared to other groups under study. Heterozygosity in the XPD gene (codon 751) increased cancer risk: OR (95% CI) = 1.36 (1.03–1.81), p = 0.031 . The frequency of the XPD 312Asn allele was significantly higher in T ≥ 2 high grade than in T ≥ 2 low grade tumors p = 0.036 ; the ERCC6 1097Val/Val genotype was strongly associated with muscle-invasive tumors. Combinations of homozygous wild type alleles occurred with the increased frequency in patients with non-muscle-invasive tumors suggesting that the maintenance of normal DNA repair activity may prevent cancer progression.
    Full-text · Article · Jan 2016 · Oxidative medicine and cellular longevity
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    • "The consequences of oxidative damage , genomic rearrangements , and strand breaks , are sensed by repair proteins ( Dizdaroglu , 2012 ) . For example , 8 - oxoG is excised by OGG1 a key component of the mitochondrial and nuclear base excision repair pathway ( Radak et al . "
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    ABSTRACT: Acute exercise increases reactive oxygen and nitrogen species generation. This phenomenon is associated with two major outcomes: (1) redox signaling and (2) macromolecule damage. Mechanistic knowledge of how exercise-induced redox signaling and macromolecule damage are interlinked is limited. This review focuses on the interplay between exercise-induced redox signaling and DNA damage, using hydroxyl radical (·OH) and hydrogen peroxide (H2O2) as exemplars. It is postulated that the biological fate of H2O2 links the two processes and thus represents a bifurcation point between redox signaling and damage. Indeed, H2O2 can participate in two electron signaling reactions but its diffusion and chemical properties permit DNA oxidation following reaction with transition metals and ·OH generation. It is also considered that the sensing of DNA oxidation by repair proteins constitutes a non-canonical redox signaling mechanism. Further layers of interaction are provided by the redox regulation of DNA repair proteins and their capacity to modulate intracellular H2O2 levels. Overall, exercise-induced redox signaling and DNA damage may be interlinked to a greater extent than was previously thought but this requires further investigation.
    Full-text · Article · Jun 2015 · Frontiers in Physiology
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    • "The oxidized guanine (8-oxodG) has great biological importance as this is a mutagenic lesion that induces G-T transversions. It may also impair DNA replication and transcription and may be an intermediate for other types of lesions in DNA [23] [33]. Substantial evidence suggests that mitochondrial DNA may be more vulnerable than nuclear DNA to certain kinds of damage, in particular, ROS-mediated lesions [31] [34] [35]. "
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    ABSTRACT: The increased production of reactive oxygen species (ROS) plays a key role in pathogenesis of diabetic complications. ROS are generated by exogenous and endogenous factors such as during hyperglycemia. When ROS production exceeds the detoxification and scavenging capacity of the cell, oxidative stress ensues. Oxidative stress induces DNA damage and when DNA damage exceeds the cellular capacity to repair it, the accumulation of errors can overwhelm the cell resulting in cell death or fixation of genome mutations that can be transmitted to future cell generations. These mutations can lead to and/or play a role in cancer development. This review aims at (i) understanding the types and consequences of DNA damage during hyperglycemic pregnancy; (ii) identifying the biological role of DNA repair during pregnancy, and (iii) proposing clinical interventions to maintain genome integrity. While hyperglycemia can damage the maternal genetic material, the impact of hyperglycemia on fetal cells is still unclear. DNA repair mechanisms may be important to prevent the deleterious effects of hyperglycemia both in mother and in fetus DNA and, as such, prevent the development of diseases in adulthood. Hence, in clinical practice, maternal glycemic control may represent an important point of intervention to prevent the deleterious effects of maternal hyperglycemia to DNA.
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