Article

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: 4.86). 01/2012; 327(1-2):26-47. DOI: 10.1016/j.canlet.2012.01.016
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
94 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The likelihood of intentional and unintentional engineered nanoparticle (ENP) exposure has dramatically increased due to the use of nanoenabled products. Indeed, ENPs have been incorporated in many useful products and have enhanced our way of life. However, there are many unanswered questions about the consequences of nanoparticle exposures, in particular, with regard to their potential to damage the genome and thus potentially promote cancer. In this study, we present a high-throughput screening assay based upon the recently developed CometChip technology, which enables evaluation of single-stranded DNA breaks, abasic sites, and alkali-sensitive sites in cells exposed to ENPs. The strategic microfabricated, 96-well design and automated processing improves efficiency, reduces processing time, and suppresses user bias in comparison to the standard comet assay. We evaluated the versatility of this assay by screening five industrially relevant ENP exposures (SiO2, ZnO, Fe2O3, Ag, and CeO2) on both suspension human lymphoblastoid (TK6) and adherent Chinese hamster ovary (H9T3) cell lines. MTT and CyQuant NF assays were employed to assess cellular viability and proliferation after ENP exposure. Exposure to ENPs at a dose range of 5, 10, and 20 μg/mL induced dose-dependent increases in DNA damage and cytotoxicity. Genotoxicity profiles of ZnO > Ag > Fe2O3 > CeO2 > SiO2 in TK6 cells at 4 h and Ag > Fe2O3 > ZnO > CeO2 > SiO2 in H9T3 cells at 24 h were observed. The presented CometChip platform enabled efficient and reliable measurement of ENP-mediated DNA damage, therefore demonstrating the efficacy of this powerful tool in nanogenotoxicity studies.
    ACS Nano 03/2014; · 12.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Watermelon is a natural product that contains high level of antioxidants and may prevent oxidative damage in tissues due to free radical generation following an exposure to ionizing radiation. The present study aimed to investigate the radioprotective effects of watermelon (Citrullus lanatus (Thunb.) Matsum. and Nakai) juice against oxidative damage induced by low dose X-ray exposure in mice. Twelve adult male ICR mice were randomly divided into two groups consisting of radiation (Rx) and supplementation (Tx) groups. Rx received filtered tap water, while Tx was supplemented with 50% (v/v) watermelon juice for 28 days ad libitum prior to total body irradiation by 100 𝜇Gy X-ray on day 29. Brain, lung, and liver tissues were assessed for the levels of malondialdehyde (MDA), apurinic/apyrimidinic (AP) sites, glutathione (GSH), and superoxide dismutase (SOD) inhibition activities. Results showed significant reduction of MDA levels and AP sites formation of Tx compared to Rx (𝑃 < 0.05). Mice supplemented with 50% watermelon juice restore the intracellular antioxidant activities by significantly increased SOD inhibition activities and GSH levels compared to Rx. These findings may postulate that supplementation of 50% watermelon (Citrullus lanatus (Thunb.) Matsum. and Nakai) juice could modulate oxidative damage induced by low dose X-ray exposure.
    BioMed Research International 04/2014; 2014(Biologic Activity and Biotechnological Development of Natural Products 2014). · 2.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genomic uracil is normally processed essentially error-free by base excision repair (BER), with mismatch repair (MMR) as an apparent backup for U:G mismatches. Nuclear uracil-DNA glycosylase UNG2 is the major enzyme initiating BER of uracil of U:A pairs as well as U:G mismatches. Deficiency in UNG2 results in several-fold increases in genomic uracil in mammalian cells. Thus, the alternative uracil-removing glycosylases, SMUG1, TDG and MBD4 cannot efficiently complement UNG2-deficiency. A major function of SMUG1 is probably to remove 5-hydroxymethyluracil from DNA with general back-up for UNG2 as a minor function. TDG and MBD4 remove deamination products U or T mismatched to G in CpG/mCpG contexts, but may have equally or more important functions in development, epigenetics and gene regulation. Genomic uracil was previously thought to arise only from spontaneous cytosine deamination and incorporation of dUMP, generating U:G mismatches and U:A pairs, respectively. However, the identification of activation-induced cytidinedeaminase (AID) and other APOBEC family members as DNA-cytosine deaminases has spurred renewed interest in the processing of genomic uracil. Importantly, AID triggers the adaptive immune response involving error-prone processing of U:G mismatches, but also contributes to B-cell lymphomagenesis. Furthermore, mutational signatures in a substantial fraction of other human cancers are consistent with APOBEC-induced mutagenesis, with U:G mismatches as prime suspects. Mutations can be caused by replicative polymerases copying uracil in U:G mismatches, or by translesion polymerases that insert incorrect bases opposite abasic sites after uracil-removal. In addition, kataegis, localized hypermutations in one strand in the vicinity of genomic rearrangements, requires APOBEC protein, UNG2 and translesion polymerase REV1. What mechanisms govern error-free versus error prone processing of uracil in DNA remains unclear. In conclusion, genomic uracil is an essential intermediate in adaptive immunity and innate antiviral responses, but may also be a fundamental cause of a wide range of malignancies.
    DNA repair 04/2014; · 4.20 Impact Factor