Crystal Structure of a DNA Duplex Containing 8-Hydroxydeoxyguanine-Adenine Base Pairs

McAuley-Hecht, Katherine E.; Leonard, Gordon A.; Gibson, Neil; Thomson, John F.; Watson, William P.; Hunter, William N.; Brown, Tom

doi:10.1021/bi00200a006

Cited by 239 publications

(240 citation statements)

References 28 publications

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“…These results are consistent with previous thermodynamic results as well as NMR and X-ray crystal structure studies (50)(51)(52), which showed that 8-oxodG can form base pairs with both dC and dA, depending on whether the damaged nucleoside adopts an anti or syn configuration about the glycosidic bond (50,51).…”

Section: Thermodynamic Studiessupporting

confidence: 93%

Synthesis and Thermodynamic Studies of Oligodeoxyribonucleotides Containing Tandem Lesions of Thymidine Glycol and 8-Oxo-2‘-deoxyguanosine

Wang

2006

Chem. Res. Toxicol.

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Thymidine glycol (Tg), which is also known as 5,6-dihydroxy-5,6-dihydrothymidine, and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) are two major types of DNA damage products induced by reactive oxygen species (ROS). Here we report the synthesis of oligodeoxyribonucleotides (ODNs) containing both Tg and 8-oxodG. The dual incorporation of the two single-base lesions was achieved by using a phosphoramidite building block of 8-oxodG with ultramild base protecting group and a building block of Tg whose nucleobase hydroxyl groups were protected with acetyl functionality. The availability of ODNs carrying neighboring 8-oxodG and Tg provided authentic substrates for assessing the formation and examining the replication and repair of this kind of tandem lesions. In addition, thermodynamic parameters derived from melting temperature data revealed that tandem lesions destabilized the double helix to a greater extent than either of the two single-base lesions alone. The thermodynamic results could offer a basis for understanding the repair of the tandem base lesions.

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Section: Thermodynamic Studiessupporting

confidence: 93%

Synthesis and Thermodynamic Studies of Oligodeoxyribonucleotides Containing Tandem Lesions of Thymidine Glycol and 8-Oxo-2‘-deoxyguanosine

Wang

2006

Chem. Res. Toxicol.

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“…2, a and b); conversely, the same lesion is recognized by hOgg1 in the anti glycosidic configuration (15). The syn configuration is thermodynamically favored over anti for an isolated oxoG nucleoside (26), but both rotamers are found in oxoG-containing duplex DNA, with syn being preferred for oxoG paired opposite A (27,28) and anti being preferred for oxoG opposite C (29,30). The ␤F-␣10 loop plays a key role in recognition of the oxoG base.…”

Section: Resultsmentioning

confidence: 99%

DNA Lesion Recognition by the Bacterial Repair Enzyme MutM

Fromme

Verdine

2003

Journal of Biological Chemistry

170

327

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MutM is a bacterial DNA glycosylase that removes the mutagenic lesion 8-oxoguanine (oxoG) from duplex DNA. The means of oxoG recognition by MutM (also known as Fpg) is of fundamental interest, in light of the vast excess of normal guanine bases present in genomic DNA. The crystal structure of a recognition-competent but catalytically inactive version of MutM in complex with oxoG-containing DNA reveals the structural basis for recognition. MutM binds the oxoG nucleoside in the syn glycosidic configuration and distinguishes oxoG from guanine by reading out the protonation state of the N7 atom. The segment of MutM principally responsible for oxoG recognition is a flexible loop, suggesting that conformational mobility influences lesion recognition and catalysis. Furthermore, the structure of MutM in complex with DNA containing an alternative substrate, dihydrouracil, demonstrates how MutM is able to recognize lesions other than oxoG.The reactive byproducts of aerobic respiration oxidize DNA to generate a number of deleterious adducts, among which the most widely studied is 8-oxoguanine (oxoG). 1 Because oxoG mispairs with adenine during replication, this oxidative lesion is a source of G⅐C to T⅐A transversion mutations. Nearly all organisms possess enzymes that safeguard against the genotoxic effects of oxoG. The oxoG resistance pathway in bacteria, known as the "GO" system, comprises three components: MutT, MutY, and MutM (1-4). MutT hydrolyzes oxo-dGTP to oxodGMP and inorganic pyrophosphate so as to prevent de novo incorporation of oxoG into the genome during DNA replication. MutY initiates the repair of misreplicated oxoG⅐A pairs in DNA by catalyzing hydrolytic excision of the adenine base. MutM (also known as Fpg) is a bifunctional DNA glycosylase/lyase that catalyzes complete excision of oxoG lesion nucleosides when paired opposite C in DNA via a complex multistep reaction cascade. Most eukaryotes possess a GO system related to that in bacteria, with orthologous versions of MutT and MutY; however, in higher organisms, MutM is replaced by the functionally analogous but structurally unrelated enzyme Ogg1 (5, 6). Orthologs of MutM have been discovered in mammals, but these do not appear to be primarily involved in oxoG repair (7-10).Recent structural studies of MutM-DNA complexes have revealed the overall architecture of the protein-DNA complex. These structures have also provided insights into the general features of lesion presentation to the MutM active site, suggesting that the oxoG nucleoside is swiveled out of the DNA helix during repair, a theme common throughout the structural biology of base excision DNA repair. A segment of the protein near the active site is disordered in the DNA-bound MutM structures lacking an oxoG nucleobase, yet is ordered in the absence of DNA, thus leading to the tantalizing suggestion that induced fit might contribute to lesion base recognition. Understanding the structural determinants of lesion recognition by MutM has been hampered by the fact that none of the available high re...

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“…The ⅐OH are believed to arise via the metal (e.g., Fe ϩ2 )-catalyzed decomposition of H 2 O 2 , such as in redox cycling of hormones (5) and xenobiotics (6). The 8-oxo lesions contribute to localized conformational changes in base pairing and vertical base stacking within the DNA helix, as suggested by x-ray diffraction studies (7)(8)(9)). …”

mentioning

confidence: 99%

“…Accordingly, it has been suggested that nucleotide-localized changes probably lead to alterations in the fidelity of DNA repair (8,11) and create synthesis errors at the replication fork (2,8,10). Until recently, almost no information existed on whether the radical-induced changes in base structure also give rise to conformational alterations in the phospho-deoxyribose backbone.…”

mentioning

confidence: 99%

Single 8-oxo-guanine and 8-oxo-adenine lesions induce marked changes in the backbone structure of a 25-base DNA strand

Malins

Polissar

Ostrander

et al. 2000

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

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Structural changes in a 25-base DNA strand, induced by single 8-oxo-guanine or 8-oxo-adenine substitutions, were shown by using Fourier transform-infrared spectroscopy with multivariate statistics. Pronounced differences were demonstrated between the parent and derivatives with respect to base interactions and changes in the phospho-deoxyribose backbone. The greatest degree of change in the backbone likely occurred immediately adjacent to the 8-oxo group, potentially altering the stereochemistry at a distance. The 8-oxo lesions, formed from reactive oxygen species (e.g., hydroxyl radicals), may appreciably alter the conformational properties of strands at the replication fork, thus affecting the selectivity of polymerases, the proofreading capability of repair enzymes, and the fidelity of the transcriptional machinery.Fourier transform-infrared spectroscopy ͉ DNA transcription ͉ DNA replication ͉ DNA repair ͉ DNA polymerases

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Crystal Structure of a DNA Duplex Containing 8-Hydroxydeoxyguanine-Adenine Base Pairs

Cited by 239 publications

References 28 publications

Synthesis and Thermodynamic Studies of Oligodeoxyribonucleotides Containing Tandem Lesions of Thymidine Glycol and 8-Oxo-2‘-deoxyguanosine

Synthesis and Thermodynamic Studies of Oligodeoxyribonucleotides Containing Tandem Lesions of Thymidine Glycol and 8-Oxo-2‘-deoxyguanosine

DNA Lesion Recognition by the Bacterial Repair Enzyme MutM

Single 8-oxo-guanine and 8-oxo-adenine lesions induce marked changes in the backbone structure of a 25-base DNA strand

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