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
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.
Available from: Harini Sampath
- "A brief overview of structure and function of each of these glycosylases is presented below. For more detailed insights into tissue specificities and regulation of these glycosylases, the reader is directed to a recent review [Sampath et al., 2012a]. Mouse models of other BER glycosylases , including the alkyladenine DNA glycosylase (AAG) and uracil DNA glycosylase have also been studied extensively with respect to various pathologies such as cancer and neurodegeneration. "
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ABSTRACT: Cellular components, including nucleic acids, are subject to oxidative damage. If left unrepaired, this damage can lead to multiple adverse cellular outcomes, including increased mutagenesis and cell death. The major pathway for repair of oxidative base lesions is the base excision repair pathway, catalyzed by DNA glycosylases with overlapping but distinct substrate specificities. To understand the role of these glycosylases in the initiation and progression of disease, several transgenic mouse models have been generated to carry a targeted deletion or overexpression of one or more glycosylases. This review summarizes some of the major findings from transgenic animal models of altered DNA glycosylase expression, especially as they relate to pathologies ranging from metabolic disease and cancer to inflammation and neuronal health. Environ. Mol. Mutagen., 2014. © 2014 Wiley Periodicals, Inc.
Available from: Pawel Jaruga
- "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 ). 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.
Available from: Romanouskaya T. V.
- "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.
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