NMR Structural Studies of DNA Decamer Duplex Containing the Dewar Photoproduct of Thymidylyl(3′→5′)Thymidine

Hwang, Geum‐Sook; Kim, Jongki; Choi, Byong‐Seok

doi:10.1111/j.1432-1033.1996.00359.x

Cited by 21 publications

(13 citation statements)

References 28 publications

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“…This structural feature is consistent with the observation of the sequential NOEs between A7-H8 and the T6 sugar protons in the (6-4)͞GA duplex. Such NOEs are absent from the structural analysis of the (6-4)͞AA duplex (23). This result implies that the 3Ј T⅐G base pair diminishes dramatically the distortion of the backbone conformation between the (6-4) lesion and its 3Ј flanking region.…”

Section: Resultsmentioning

confidence: 97%

Solution structure of a DNA decamer duplex containing the stable 3′ T⋅G base pair of the pyrimidine(6–4)pyrimidone photoproduct [(6–4) adduct]: Implications for the highly specific 3′ T → C transition of the (6–4) adduct

Lee

Hwang

Choi

1999

Proc. Natl. Acad. Sci. U.S.A.

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The pyrimidine(6-4)pyrimidone photoproduct [(6-4) adduct] is one of the major photoproducts induced by UV irradiation of DNA and occurs at TpT sites. The (6-4) adduct is highly mutagenic and leads most often to a 3 T 3 C transition with 85% replicating error frequency [LeClerc, J. E., Borden, A. & Lawrence, C. W. (1991) Proc. Natl. Acad. Sci. USA 88, 9685-9689]. To determine the origin of the specific 3 T 3 C transition of the (6-4) adduct, we have used experimental NMR restraints and molecular dynamics to determine the solution structure of a (6-4)-lesion DNA decamer duplex that contains a mismatched base pair between the 3 T residue and an opposed G residue. Normal WatsonCrick-type hydrogen bonding is retained at the 5 T of the lesion site. The O2 carbonyl of the 3 T residue forms hydrogen bonds with the imino and amino protons of the opposed G residue. This potential hydrogen bonding stabilizes the overall helix and restores the highly distorted conformation of the (6-4) adduct to the typical B-form-like DNA structure. This structural feature can explain the marked preference for the insertion of an A residue opposite the 5 T and a G residue opposite the 3 T of the (6-4) lesion during trans-lesion synthesis. Thus these insertions yield the predominant 3 T 3 C transition.UV light irradiation of DNA produces a variety of photoproducts that cause mutations to be introduced in the DNA and ultimately the development of various cancers (1-4). The cis-syn cyclobutane pyrimidine dimer (cis-syn dimer) and pyrimidine(6-4)pyrimidone photoproduct [(6-4) adduct] (Fig. 1A) constitute the two major classes of UV-induced DNA photoproducts and occur at TpT sites in the DNA (5, 6). The cis-syn dimer, which is the most abundant photoproduct, has a much lower repair rate for the DNA repair enzymes than does the (6-4) adduct. The cis-syn dimer undergoes excision repair in vivo with a half-life of Ϸ24 hr, whereas the (6-4) adduct is repaired rapidly with a half-life of Ϸ4 hr (7). In vitro, the cis-syn dimer is repaired about nine times slower than the (6-4) adduct by the Escherichia coli uvr(A)BC endonuclease (8). The binding affinities of the DNA damage binding proteins (for example, uvrA subunit, human damaged DNA binding protein, and human replicating protein A) for the cis-syn dimer are also much lower than those for the (6-4) adduct (9, 10). However, cis-syn dimer displays a very low mutagenic rate (11)(12)(13)(14). Structural studies of a DNA decamer duplex containing a cis-syn dimer suggest that the formation of Watson-Crick base pairs between the two T residues and the corresponding A residues could explain the low mutagenecity of the dimer (15).Although the T-T (6-4) adduct is collectively 5-to 10-fold less abundant in UV-irradiated DNA and is more rapidly repaired than the cis-syn dimer, the (6-4) adduct is highly mutagenic and yields a specific mutation (13,14,16). In SOS-induced E. coli cells, adenine was found to be incorporated into the site opposite the 5Ј T of the (6-4) adduct with a frequency of 95% (16)....

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Section: Resultsmentioning

confidence: 97%

Solution structure of a DNA decamer duplex containing the stable 3′ T⋅G base pair of the pyrimidine(6–4)pyrimidone photoproduct [(6–4) adduct]: Implications for the highly specific 3′ T → C transition of the (6–4) adduct

Lee

Hwang

Choi

1999

Proc. Natl. Acad. Sci. U.S.A.

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“…The formation of 6-4PPs and their Dewar isomers cause remarkable change in the conformation of DNA duplex. The one- and two-dimensional NMR data on the (6-4)-adduct-containing DNA duplex decamer was analyzed in H 2 O and D 2 O solutions to elicit the base pairing and unusual conformation in the vicinity of the lesion [76, 83, 84]. The distortion of the double helix caused by the 6-4PP is much greater than that of the CPD [85].…”

Section: Differential Effects Of Cpds and 6-4pps On Dna Conformationmentioning

confidence: 99%

Molecular Mechanisms of Ultraviolet Radiation‐Induced DNA Damage and Repair

Rastogi

Richa

Kumar

et al. 2010

Journal of Nucleic Acids

971

735

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DNA is one of the prime molecules, and its stability is of utmost importance for proper functioning and existence of all living systems. Genotoxic chemicals and radiations exert adverse effects on genome stability. Ultraviolet radiation (UVR) (mainly UV-B: 280–315 nm) is one of the powerful agents that can alter the normal state of life by inducing a variety of mutagenic and cytotoxic DNA lesions such as cyclobutane-pyrimidine dimers (CPDs), 6-4 photoproducts (6-4PPs), and their Dewar valence isomers as well as DNA strand breaks by interfering the genome integrity. To counteract these lesions, organisms have developed a number of highly conserved repair mechanisms such as photoreactivation, base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Additionally, double-strand break repair (by homologous recombination and nonhomologous end joining), SOS response, cell-cycle checkpoints, and programmed cell death (apoptosis) are also operative in various organisms with the expense of specific gene products. This review deals with UV-induced alterations in DNA and its maintenance by various repair mechanisms.

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“…2. Imino protons of U5 and U6 were resonated at 11.87 and 13.16 ppm, respectively, and they were similar to the frequencies of T5 and T6 in the TT CBD/AA (25,26). Sequential NOE of imino protons showed a relatively weak connectivity at the 3′ side of the dimer, although no disconnection was found.…”

Section: Resultsmentioning

confidence: 66%

“…Resonance assignments of the photochemically modified duplex were easy to interpret by referring to previous NMR studies of the photochemically modified duplex with normal Watson–Crick base pairing at the T cis – syn CBD site (25,26). The chemical shifts of the central four nucleotides in both the UU and the TT dimer duplexes were summarized and compared in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…But the observed mutational spectrum of the UV lesion suggests that the chemical structure of the lesion and its effects on local DNA conformation are more important information that a DNA polymerase actually exploits as coding information in the addition step. A series of data from experimental studies on the structural perturbation of photodimer and photoadduct in nucleic acids has been built up, suggesting relatively different overall structural distortions depending on the DNA photolesions (22–31). It is interesting to see how the missensed nucleotide fits opposite a specific UV lesion within the duplex DNA.…”

Section: Introductionmentioning

confidence: 99%

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1H-NMR Studies of Duplex DNA Decamer Containing a Uracil Cyclobutane Dimer: Implications Regarding the High UV Mutagenecity of CC Photolesions¶

Lee

Kim²

2007

Photochemistry and Photobiology

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To determine the origin of the UV‐specific CC to TT tandem mutation at the CC site, we made a duplex DNA decamer containing a uracil cis–syn cyclobutane dimer (CBD) as the deaminated model of a cytosine dimer. Two‐dimensional 1H‐NMR spectroscopy studies were performed on this sequence where two adenines (Ade) were opposite to the uracil dimer. Two imino protons of the uracil dimer were found to retain Watson–Crick hydrogen bonding with the opposite Ade, although the 5′‐U(NH) of the dimer site showed unusual upfield shift like that of the 5′‐T(NH) of the TT dimer, which seemed to be associated with deshielding by the flanking base rather than with reduced hydrogen bonding. (McAteer et al. 1998, J. Mol. Biol. 282:1013–1032). Hydrogen bondings at the dimer site were also supported by detecting typical strong nuclear Overhauser effects (NOE) between two imino protons and the opposite Ade H2 or NH2. But sequential NOE interactions of base protons with sugar protons were absent at the two flanking nucleotides of the 5′ side of the uracil dimer and at the intradimer site, contrasting with its thymine analog where sequential NOE was absent only at the A4–T5 step. In addition, NOE cross peak for U5(NH) ↔ A4(H2) was detected, although the NOE interactions of U6(NH) with A7(H2) and A17(H2) were not observed in contrast to the thymine dimer duplex. This different local structural alteration may be affected by the induced right‐hand twisted puckering mode of cis–syn cyclobutane ring of the uracil dimer in the B‐DNA duplex, even though the isolated uracil dimer had left‐hand twisted puckering rigidly. In parallel, these observations may be correlated with observed differences in mutagenic properties between cis–syn UU dimer and cis–syn TT dimer.

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NMR Structural Studies of DNA Decamer Duplex Containing the Dewar Photoproduct of Thymidylyl(3′→5′)Thymidine

Cited by 21 publications

References 28 publications

Solution structure of a DNA decamer duplex containing the stable 3′ T⋅G base pair of the pyrimidine(6–4)pyrimidone photoproduct [(6–4) adduct]: Implications for the highly specific 3′ T → C transition of the (6–4) adduct

Solution structure of a DNA decamer duplex containing the stable 3′ T⋅G base pair of the pyrimidine(6–4)pyrimidone photoproduct [(6–4) adduct]: Implications for the highly specific 3′ T → C transition of the (6–4) adduct

Molecular Mechanisms of Ultraviolet Radiation‐Induced DNA Damage and Repair

1H-NMR Studies of Duplex DNA Decamer Containing a Uracil Cyclobutane Dimer: Implications Regarding the High UV Mutagenecity of CC Photolesions¶

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