Assignment of Absolute Configurations of the Enantiomeric Spiroiminodihydantoin Nucleobases by Experimental and Computational Optical Rotatory Dispersion Methods

Durandin, Alexander; Jia, Lei; Crean, Conor; Kolbanovskiy, Alexander; Ding, Shuang; Shafirovich, Vladimir; Broyde, Suse; Geacintov, Nicholas E.

doi:10.1021/tx060078e

Cited by 33 publications

(76 citation statements)

References 59 publications

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“…From our data and the modeling studies, it is tempting to suggest that the R diastereomer is Sp2, while S is the Sp1 diastereomer. (Figure 5) However, we note that naming of Sp1 and Sp2 is based on elution order of Sp-containing oligonucleotides on an ion exchange column which may not correlate to the same Sp1 and Sp2 assignments of nucleosides on a Hypercarb (graphite) HPLC column (51,52). Further work is necessary to confirm the R and S designations of the monomer and oligomers.…”

Section: Discussionmentioning

confidence: 91%

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

et al. 2008

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The DNA glycosylase hNEIL1 initiates the base excision repair (BER) of a diverse array of lesions, including ring-opened purines and saturated pyrimidines. Of these, the hydantoin lesions, guanidinohydantoin (Gh) and the two diastereomers of spiroiminodihydantoin (Sp1 and Sp2) have garnered much recent attention due to their unusual structures, high mutagenic potential and detection in cells. In order to provide insight into the role of repair, the excision efficiency by hNEIL1 of these hydantoin lesions relative to other known substrates was determined. Most notably, quantitative examination of the substrate specificity with hNEIL1 revealed that the hydantoin lesions are excised much more efficiently (> 100-fold faster) than the reported standard substrates thymine glycol (Tg) and 5-hydroxycytosine (5-OHC). Importantly, the glycosylase and β,δ-lyase reactions are tightly coupled such that the rate of the lyase activity does not influence the observed substrate specificity. The activity of hNEIL1 is also influenced by the base pair partner of the lesion, with both Gh and Sp removal being more efficient when paired with T, G or C than when paired with A. Notably, the most efficient removal is observed with the Gh or Sp paired in the unlikely physiological context with T; indeed, this may be a consequence of the unstable nature of base pairs with T. However, the facile removal via BER in promutagenic base pairs that are reasonably formed after replication (such as Gh:G) may be a factor that modulates the mutagenic profile of these lesions. In addition, hNEIL1 excises Sp1 faster than Sp2 indicating the enzyme can discriminate between the two diastereomers. This is the first time that a BER glycosylase has been shown to be able to preferentially excise one diastereomer of Sp. This may be a consequence of the architecture of the active site of hNEIL1 and the structural uniqueness of the Sp lesion. These results indicate that the hydantoin lesions are the best substrates identified thus far for hNEIL1, and suggest that repair of these lesions may be a critical function of the hNEIL1 enzyme in vivo.Cells experiencing oxidative stress have an overabundance of reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals (1,2). ROS are present in cells as byproducts of endogenous metabolic reactions or as a result of external sources such as ionizing radiation. The reactions mediated by ROS can lead to various types of DNA damage including strand breaks, DNA-protein cross-links, abasic sites, and base lesions, which are potentially detrimental to cells (3)(4)(5)(6). Oxidative DNA damage is mitigated by a variety of DNA repair pathways (7-9). The importance of repairing DNA damage has been highlighted by the correlation between defects in DNA repair pathways and cancer (7,(10)(11)(12). ¶ This work was supported by a grant from the National Cancer Institute of the National Institutes of Health (CA90689). Although a variety of guanine oxidation products have been identified (13), most st...

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Section: Discussionmentioning

confidence: 91%

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

et al. 2008

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“…Finally, an excellent correlation between our experimental NMR data and the quantum mechanics calculations recently reported by Broyde et al (30,31) should be pointed out. During the preparation of the manuscript, we have been informed of the determination of the absolute configuration of 1 and 2 that was achieved using a different strategy (41). However, this, which is based on theoretical calculations of ORD features, has led to opposite conclusions and it is not clear at the present stage what is at the origin of the observed discrepancies in the assignment of the stereochemistry of the spirocyclic carbon of 1 and 2.…”

Section: Resultsmentioning

confidence: 99%

Nuclear Magnetic Resonance Studies of the 4R and 4S Diastereomers of Spiroiminodihydantoin 2‘-Deoxyribonucleosides: Absolute Configuration and Conformational Features

Karwowski

Dupeyrat

Bardet

et al. 2006

Chem. Res. Toxicol.

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The present study was aimed at gaining further insights into stereochemical and conformational features of the 4R and 4S diastereomers of spiroiminodihydantoin 2'-deoxyribonucleosides that have been shown to be the predominant singlet oxygen oxidation products of 2'-deoxyguanosine in aqueous solutions. It may be added that spiroiminodihydantoin derivatives are efficiently generated by one-electron and singlet oxygen oxidation of the 8-oxo-7,8-dihydroguanine moiety of several nucleic acid components including nucleosides, nucleotides, and oligonucleotides. The reported structural data on the pair of diastereomeric spiroiminodihydantoin 2'-deoxyribonucleosides 1 and 2 are mostly inferred from extensive (1)H and (13)C NMR analyses including two-dimensional nuclear Overhauser effect measurements performed in both D(2)O and dimethyl sulfoxide. This approach that has been shown previously to be suitable to assign the stereochemistry of the base moiety of oxidized pyrimidine nucleosides was completed by molecular modeling and quantum mechanics studies. Thus, application of these two complementary approaches together with the consideration of the results of a recent relevant quantum mechanic study has allowed the assignment of the absolute stereoconfiguration of the C-4 carbon of diastereomers 1 and 2. In addition, information is provided on the conformational features of the 2-deoxyribose moiety and the orientation of the base around the N-glycosidic bond of both 2'-deoxyribonucleosides 1 and 2.

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“…Although two groups recently reported assignment of the absolute stereochemistry of the Sp diastereomers, they arrived at opposite conclusions leaving the true stereochemical assignment as an issue that awaits resolution (54,55). Jia et al (56) performed a computational study of duplexes containing the Sp diastereomers.…”

Section: Discussionmentioning

confidence: 99%

DNA Polymerase V Allows Bypass of Toxic Guanine Oxidation Products in Vivo

Neeley

Delaney

Alekseyev

et al. 2007

Journal of Biological Chemistry

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Reactive oxygen and nitrogen radicals produced during metabolic processes, such as respiration and inflammation, combine with DNA to form many lesions primarily at guanine sites. Understanding the roles of the polymerases responsible for the processing of these products to mutations could illuminate molecular mechanisms that correlate oxidative stress with cancer. Using M13 viral genomes engineered to contain single DNA lesions and Escherichia coli strains with specific polymerase (pol) knockouts, we show that pol V is required for efficient bypass of structurally diverse, highly mutagenic guanine oxidation products in vivo. We also find that pol IV participates in the bypass of two spiroiminodihydantoin lesions. Furthermore, we report that one lesion, 5-guanidino-4-nitroimidazole, is a substrate for multiple SOS polymerases, whereby pol II is necessary for error-free replication and pol V for error-prone replication past this lesion. The results spotlight a major role for pol V and minor roles for pol II and pol IV in the mechanism of guanine oxidation mutagenesis.The genome is continually damaged by spontaneously generated and environmental chemical agents. Many of the lesions formed in DNA strongly inhibit replicative polymerases. If repair of these lesions fails or is not fast enough, cells can biochemically adapt to "tolerate" the toxic DNA lesions, as evidenced by replication of the damaged DNA (1). Human cells possess at least 15 DNA polymerases, including 5 that are referred to as translesion synthesis (TLS) 3 polymerases and are specifically involved in the replication of damaged DNA. Four of these enzymes, pol , pol , pol , and REV1, belong to the Y family of DNA polymerases, whereas pol belongs to the B family (2). Escherichia coli possess three polymerases, pol II, pol IV, and pol V, whose expression levels are up-regulated in response to DNA damage. Extensive research on the structure and function of these polymerases and their homologues suggests that these polymerases allow replication to progress in the presence of DNA lesions that are strongly inhibitory to the replicative polymerase, pol III (1). The presence of the three SOSinducible polymerases allows E. coli to be used as a model system for DNA replication past damage products.pol II (pol B) (3) is a B family DNA polymerase and has 3Ј 3 5Ј-exonuclease activity. Consequently, this enzyme replicates normal DNA with high fidelity and has an error rate less of than 10 Ϫ6 (4). pol II participates in error-free replication restart (5, 6) and can also carry out TLS past abasic sites (3, 7), 3,N 4 -ethenocytosine (8), and N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (9). pol IV (DinB) (10) and pol V (UmuD 2 ЈC) (11) are members of the Y family of DNA polymerases, which have less sterically restrictive active sites than normal replicative polymerases (12) and lack exonuclease activity (1). The error rates of these polymerases are much higher than the other E. coli polymerases and are on the order of 10 Ϫ4 to 10 Ϫ5 for pol IV (13) and 10 Ϫ3 to 10 Ϫ4...

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Assignment of Absolute Configurations of the Enantiomeric Spiroiminodihydantoin Nucleobases by Experimental and Computational Optical Rotatory Dispersion Methods

Cited by 33 publications

References 59 publications

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

Nuclear Magnetic Resonance Studies of the 4R and 4S Diastereomers of Spiroiminodihydantoin 2‘-Deoxyribonucleosides: Absolute Configuration and Conformational Features

DNA Polymerase V Allows Bypass of Toxic Guanine Oxidation Products in Vivo

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