Photoinduced deoxyribose C2' oxidation in DNA. Alkali-dependent cleavage of erythrose-containing sites via a retroaldol reaction

Sugiyama, Hiroshi; Tsutsumi, Yoshitaka; Fujimoto, Kenzo; Saito, Isao

doi:10.1021/ja00064a004

Cited by 98 publications

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“…These species include the hydroxyl radical, the product formed from water by γ-radiolysis, and the sigma radicals formed upon irradiation of 5-halopyrimdines in DNA (11)(12)(13)(14)(15). Until recently, when a method for synthesizing oligonucleotides containing C2-AP was reported, little was known about the lesion's biochemical effects (16).…”

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confidence: 99%

Replication of an Oxidized Abasic Site in Escherichia coli by a dNTP-Stabilized Misalignment Mechanism that Reads Upstream and Downstream Nucleotides

et al. 2006

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Abasic sites (AP) and oxidized abasic lesions are often referred to as noninstructive lesions because they cannot participate in Watson-Crick base pairing. The aptness of the term noninstructive for describing AP site replication has been called into question by recent investigations in E. coli using single-stranded shuttle vectors. These studies revealed that the replication of templates containing AP sites or the oxidized abasic lesions resulting from C1′-(L) and C4′-oxidation (C4-AP) are distinct from one another, suggesting that structural features other than Watson-Crick hydrogen bonds contribute to controlling replication. The first description of the replication of the abasic site resulting from formal C2′-oxidation (C2-AP) is presented here. Full-length and single-nucleotide deletion products are observed when templates containing C2-AP are replicated in E. coli. Single nucleotide deletion formation is largely dependent upon the concerted effort of pol II and pol IV, whereas pol V suppresses frameshift product formation. Pol V utilizes the A-rule when bypassing C2-AP. In contrast, pol II and pol IV utilize a dNTP-stabilized misalignment mechanism to read the upstream and downstream nucleotides when bypassing C2-AP. This is the first example in which the identity of the 3′-adjacent nucleotide is read during the replication of a DNA lesion. The results raise further questions as to whether abasic lesions are noninstructive lesions. We suggest that abasic site bypass is affected by the local biopolymer structure in addition to the structure of the lesion.Abasic sites (AP 1 ), the most common DNA lesions formed, are produced in a variety of ways in DNA, including as intermediates during base excision repair (1-3). In addition, a variety of oxidized abasic lesions are produced when DNA is exposed to oxidative stress. DNA damaging agents selectively produce oxidized abasic lesions, including 2-deoxyribonolactone (L), and the C4′-oxidized abasic site (C4-AP) (Figure 1) (4-7). These agents take advantage of the accessibility and/or relatively low bond strength of the respective carbon-hydrogen bonds (8-10). The C2′-carbon-hydrogen bond is the strongest of the deoxyribose bonds in DNA. Consequently, the C2-AP lesion is only produced by highly reactive species, presumably via † Supported by NIGMS grants GM-063028 to M.M.G. and ES-012259 and GM-021422 to M.F.G. * To whom correspondence should addressed. . E-mail: mgreenberg@jhu.edu.. ‡ Johns Hopkins University. § University of Southern California.SUPPORTING INFORMATION AVAILABLE ESI-MS of the oligonucleotides (3) containing C2-AP used to prepare the single-stranded plasmids and a figure describing the REAP experiment. This material is available free of charge via the Internet at http://pubs.acs.org. 1 Abbreviations: C2′-oxidized abasic site, C2-AP; C4′-oxidized abasic site, C4-AP; abasic site, AP; 2-deoxyribonolactone, L; tetrahydrofuran abasic site model, F; polyacrylamide gel electrophoresis, PAGE; DNA polymerase II, pol II; DNA polymerase IV, pol IV; DNA...

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confidence: 99%

Replication of an Oxidized Abasic Site in Escherichia coli by a dNTP-Stabilized Misalignment Mechanism that Reads Upstream and Downstream Nucleotides

et al. 2006

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“…38,57,58 Formation of the C2′-oxidized abasic site ( 18 ) is attributed to O 2 trapping of the radical produced upon C2′-hydrogen atom abstraction. 41 The details for obtaining 18 from the peroxyl radical are uncertain, including the identity of the reducing agent. A Criegée rearrangement is drawn here but the original report suggested a different mechanism.…”

Section: C2′-radical Generation and Reactivity In Dna Ribonucleosmentioning

confidence: 99%

Reactivity of Nucleic Acid Radicals

Greenberg

2016

Advances in Physical Organic Chemistry

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Nucleic acid oxidation plays a vital role in the etiology and treatment of diseases, as well as aging. Reagents that oxidize nucleic acids are also useful probes of the biopolymers’ structure and folding. Radiation scientists have contributed greatly to our understanding of nucleic acid oxidation using a variety of techniques. During the past two decades organic chemists have applied the tools of synthetic and mechanistic chemistry to independently generate and study the reactive intermediates produced by ionizing radiation and other nucleic acid damaging agents. This approach has facilitated resolving mechanistic controversies and lead to the discovery of new reactive processes.

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“…In recent years, there has been substantial interest in the development of biomimetic nucleases, especially for DNA cleavage [8][9][10][11][12][13][14][15][16][17][18][19][20]. The primary motivation for such efforts reflects the desire to develop anticancer or footprinting agents, with the former most likely influenced by bleomycin, an anticancer drug that suffers from significant toxicity levels.…”

Section: Development Of Biomimetic Nucleases and Proteasesmentioning

confidence: 99%

Catalytic metallodrugs

Cowan

2008

Pure and Applied Chemistry

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Drug discovery remains a top priority in medical science. The phenomenon of drug resistance has heightened the need for both new classes of pharmaceutical, as well as novel modes of action. A new paradigm for drug activity is presented, which includes both recognition and subsequent irreversible inactivation of therapeutic targets. Application to both RNA and enzyme therapeutic targets has been demonstrated, while incorporation of both binding and catalytic centers provides a double-filter mechanism for improved target selectivity and lower dosing. In contrast to RNA targets that are subject to strand scission chemistry mediated by ribose H-atom abstraction, proteins appear to be inactivated through oxidative damage to amino acid side chains around the enzyme active site. Methods to monitor both intracellular delivery and activity against RNA targets have been developed based on plasmid expression of the green fluorescent protein (GFP). Herein, the activity of representative metallodrugs is described in the context of both in vitro and cellular assays, and the mechanism of action is discussed. Studies with scavengers of reactive oxygen species (ROS) confirmed hydrogen peroxide to be an obligatory diffusible intermediate, prior to formation of a Cu-bound hydroxyl radical species generated from Fenton-type chemistry.

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Photoinduced deoxyribose C2' oxidation in DNA. Alkali-dependent cleavage of erythrose-containing sites via a retroaldol reaction

Cited by 98 publications

References 0 publications

Replication of an Oxidized Abasic Site in Escherichia coli by a dNTP-Stabilized Misalignment Mechanism that Reads Upstream and Downstream Nucleotides

Replication of an Oxidized Abasic Site in Escherichia coli by a dNTP-Stabilized Misalignment Mechanism that Reads Upstream and Downstream Nucleotides

Reactivity of Nucleic Acid Radicals

Catalytic metallodrugs

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