Regulation of DNA glycosylases and their role in limiting disease

Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, Oregon 97239 - 3098, USA.
Free Radical Research (Impact Factor: 2.98). 02/2012; 46(4):460-78. DOI: 10.3109/10715762.2012.655730
Source: PubMed


This review will present a current understanding of mechanisms for the initiation of base excision repair (BER) of oxidatively-induced DNA damage and the biological consequences of deficiencies in these enzymes in mouse model systems and human populations.

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    • "The DNA base excision repair (BER) pathway has evolved to respond to ongoing challenges to genome stability that are posed by oxidation, alkylation, and deamination of DNA bases. In humans, the initiation of BER of DNA damage arising from oxidative stress occurs through the collective activities of the DNA glycosylases NEIL1, NEIL2, NEIL3, OGG1, and NTH1 (reviewed in [1]). Through a series of sequential biochemical steps, these enzymes flip the damaged nucleotide to an extrahelical position and catalyze removal of the damaged base through glycosyl bond scission, followed by phosphodiester bond breakage. "
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    ABSTRACT: Following the formation of oxidatively-induced DNA damage, several DNA glycosylases are required to initiate repair of the base lesions that are formed. Recently, NEIL1 and other DNA glycosylases, including OGG1 and NTH1 were identified as potential targets in combination chemotherapeutic strategies. The potential therapeutic benefit for the inhibition of DNA glycosylases was validated by demonstrating synthetic lethality with drugs that are commonly used to limit DNA replication through dNTP pool depletion via inhibition of thymidylate synthetase and dihydrofolate reductase. Additionally, NEIL1-associated synthetic lethality has been achieved in combination with Fanconi anemia, group G. As a prelude to the development of strategies to exploit the potential benefits of DNA glycosylase inhibition, it was necessary to develop a reliable high-throughput screening protocol for this class of enzymes. Using NEIL1 as the proof-of-principle glycosylase, a fluorescence-based assay was developed that utilizes incision of site-specifically modified oligodeoxynucleotides to detect enzymatic activity. This assay was miniaturized to a 1536-well format and used to screen small molecule libraries for inhibitors of the combined glycosylase/AP lyase activities. Among the top hits of these screens were several purine analogs, whose postulated presence in the active site of NEIL1 was consistent with the paradigm of NEIL1 recognition and excision of damaged purines. Although a subset of these small molecules could inhibit other DNA glycosylases that excise oxidatively-induced DNA adducts, they could not inhibit a pyrimidine dimer-specific glycosylase.
    PLoS ONE 12/2013; 8(12):e81667. DOI:10.1371/journal.pone.0081667 · 3.23 Impact Factor
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    • "Cell Biol Int 37 (2013) 1023–1037 ß 2013 International Federation for Cell Biology reparation (to the detriment of other processes) and large quantity of reparation protein complexes along genomic DNA would interfere with other matrix processes. Meanwhile , the decrease in the number of nucleotide changes would not substantially elevate cell stability parameters (Fagbemi et al., 2011; Wilson et al., 2011; Sampath et al., 2012). However, in non-physiological conditions (e.g. in elevated radiation background, or under oxidative stress) when the frequency of structural disturbances in genomic DNA sharply increases, the reparative system activity increases. "
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    ABSTRACT: Ample adaptive and functional opportunities of a living cell are determined by the complexity of its structural organization. However, such complexity gives rise to a problem of maintenance of the coherence of inner processes in macroscopic interims and in macroscopic volumes which is necessary to support the structural robustness of a cell. The solution to this problem lies in multidimensional control of the adaptive and functional changes of a cell as well as its self-renewing processes in the context of environmental conditions. Six mechanisms (principles) form the basis of this multidimensional control: regulatory circuits with feedback loops, redundant inner diversity within a cell, multilevel distributed network organization of a cell, molecular selection within a cell, continuous informational flows and functioning with a reserve of power. In the review we provide detailed analysis of these mechanisms, discuss their specific functions and the role of these mechanisms' superposition in the maintenance of cell structural robustness in a wide range of environmental conditions.
    Cell Biology International 10/2013; 37:1023-1037. DOI:10.1002/cbin.10128 · 1.93 Impact Factor
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    • "OGG1, a DNA repair glycosylase that localizes to both the nucleus and mitochondria, is the main enzyme responsible for identification and excision of 8-oxoG lesions [5]–[9]. OGG1 is hypothesized to play a role in several disease pathways, including various cancers [4], [10]–[16], neurological diseases such as Parkinson’s [17]–[19] and Alzheimers’ [20]–[24] disease, and aging-related pathologies [25]–[28]. A common link between these pathologies is the presence of elevated levels of oxidative stress. "
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    ABSTRACT: Oxidative damage to DNA is mainly repaired via base excision repair, a pathway that is catalyzed by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). While OGG1 has been implicated in maintaining genomic integrity and preventing tumorigenesis, we report a novel role for OGG1 in altering cellular and whole body energy homeostasis. OGG1-deficient (Ogg1(-/-)) mice have increased adiposity and hepatic steatosis following exposure to a high-fat diet (HFD), compared to wild-type (WT) animals. Ogg1(-/-) animals also have higher plasma insulin levels and impaired glucose tolerance upon HFD feeding, relative to WT counterparts. Analysis of energy expenditure revealed that HFD-fed Ogg1(-/-) mice have a higher resting VCO(2) and consequently, an increased respiratory quotient during the resting phase, indicating a preference for carbohydrate metabolism over fat oxidation in these mice. Additionally, microarray and quantitative PCR analyses revealed that key genes of fatty acid oxidation, including carnitine palmitoyl transferase-1, and the integral transcriptional co-activator Pgc-1α were significantly downregulated in Ogg1(-/-) livers. Multiple genes involved in TCA cycle metabolism were also significantly reduced in livers of Ogg1(-/-) mice. Furthermore, hepatic glycogen stores were diminished, and fasting plasma ketones were significantly reduced in Ogg1(-/-) mice. Collectively, these data indicate that OGG1 deficiency alters cellular substrate metabolism, favoring a fat sparing phenotype, that results in increased susceptibility to obesity and related pathologies in Ogg1(-/-) mice.
    PLoS ONE 12/2012; 7(12):e51697. DOI:10.1371/journal.pone.0051697 · 3.23 Impact Factor
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