Mechanisms of Formation, Genotoxicity, and Mutation of Guanine Oxidation Products

Department of Chemistry and Biological Engineering Division, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Chemical Research in Toxicology (Impact Factor: 3.53). 05/2006; 19(4):491-505. DOI: 10.1021/tx0600043
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    • ", 2004 ) . The low redox potential of guanine makes this base particularly vulnerable and leads to the generation of various oxidized guanine products ( Neeley and Essigmann , 2006 ; David et al . , 2007 ) such as 8 - oxo - 7 , 8 - dihydroguanine ( 8 - oxoG ) . "
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    ABSTRACT: Ultraviolet radiation can damage biomolecules, with detrimental or even lethal effects for life. Even though lower wavelengths are filtered by the ozone layer, a significant amount of harmful UV-B and UV-A radiation reach Earth's surface, particularly in high altitude environments. high-altitude Andean lakes (HAALs) are a group of disperse shallow lakes and salterns, located at the Dry Central Andes region in South America at altitudes above 3,000 m. As it is considered one of the highest UV-exposed environments, HAAL microbes constitute model systems to study UV-resistance mechanisms in environmental bacteria at various complexity levels. Herein, we present the genome sequence of Acinetobacter sp. Ver3, a gammaproteobacterium isolated from Lake Verde (4,400 m), together with further experimental evidence supporting the phenomenological observations regarding this bacterium ability to cope with increased UV-induced DNA damage. Comparison with the genomes of other Acinetobacter strains highlighted a number of unique genes, such as a novel cryptochrome. Proteomic profiling of UV-exposed cells identified up-regulated proteins such as a specific cytoplasmic catalase, a putative regulator, and proteins associated to amino acid and protein synthesis. Down-regulated proteins were related to several energy-generating pathways such as glycolysis, beta-oxidation of fatty acids, and electronic respiratory chain. To the best of our knowledge, this is the first report on a genome from a polyextremophilic Acinetobacter strain. From the genomic and proteomic data, an "UV-resistome" was defined, encompassing the genes that would support the outstanding UV-resistance of this strain.
    Frontiers in Microbiology 04/2015; 6:328. DOI:10.3389/fmicb.2015.00328 · 3.99 Impact Factor
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    • "Thus, it is well known that 8-OH-Gua has a lower reduction potential (0.74 V) than guanine (1.29 V), meaning that it is even more prone to oxidation than guanine [20]. Indeed, the oxidation of 8-OH-Gua gives rise to its radical cation (8-OH-Gua ⦁ ), the further reactions of which generate spiroiminohydantoin (Sp) and 5-guanidinohydantoin (Gh) [21] [22] [23] [24] [25] [26] [27]. Thus, the mounting evidence stands in stark contrast to the so-called " correct " or " established " value recommended by ESCODD for the background level of 8-OH-Gua in all living organisms. "
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    ABSTRACT: Oxidatively induced damage caused by free radicals and other DNA-damaging agents generate a plethora of products in the DNA of living organisms. There is mounting evidence for the involvement of this type of damage in the etiology of numerous diseases including carcinogenesis. For a thorough understanding of the mechanisms, cellular repair, and biological consequences of DNA damage, accurate measurement of resulting products must be achieved. There are various analytical techniques, with their own advantages and drawbacks, which can be used for this purpose. Mass spectrometric techniques with isotope dilution, which include gas chromatography (GC) and liquid chromatography (LC), provide structural elucidation of products and ascertain accurate quantification, which are absolutely necessary for reliable measurement. Both gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS), in single or tandem versions, have been used for the measurement of numerous DNA products such as sugar and base lesions, 8,5’-cyclopurine-2’-deoxynucleosides, base-base tandem lesions, and DNA-protein crosslinks, in vitro and in vivo. This article reviews these techniques and their applications in the measurement of oxidatively induced DNA damage and its repair.
    Free Radical Research 03/2015; 49(5). DOI:10.3109/10715762.2015.1014814 · 2.98 Impact Factor
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    • "Guanine has the lowest redox potential of the four bases and readily oxidizes to 8-oxoG, which is probably the most highly studied base lesion although FapyG is likely to be at least as important [Liu et al., 2010]. 8-oxoG also turns out to have a lower redox potential than any of the four normal bases and can be further oxidized to a number of products ; the most studied are spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh) [for reviews, see Neeley and Essigmann, 2006; Burrows, 2009]. 2-Hydroxyadenine can also be formed by hydroxyl radical attack at the C2 position of adenine [Lesiak and Wheeler, 1990]. "
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    ABSTRACT: This review article presents, an overview of the DNA glycosylases that recognize oxidized DNA bases using the Fpg/Nei family of DNA glycosylases as models for how structure can inform function. For example, even though human NEIL1 and the plant and fungal orthologs lack the zinc finger shown to be required for binding, DNA crystal structures revealed a "zincless finger" with the same properties. Moreover, the "lesion recognition loop" is not involved in lesion recognition, rather, it stabilizes 8-oxoG in the active site pocket. Unlike the other Fpg/Nei family members, Neil3 lacks two of the three void-filling residues that stabilize the DNA duplex and interact with the opposite strand to the damage which may account for its preference for lesions in single-stranded DNA. Also single-molecule approaches show that DNA glycosylases search for their substrates in a sea of undamaged DNA by using a wedge residue that is inserted into the DNA helix to probe for the presence of damage. Environ. Mol. Mutagen., 2013. © 2013 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 12/2013; 54(9). DOI:10.1002/em.21820 · 2.63 Impact Factor
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