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Synthesis and thermodynamic studies of oligodeoxyribonucleotides containing tandem lesions of thymidine glycol and 8-oxo-2'-deoxyguanosine.

ABSTRACT: 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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC2533691 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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Synthesis and thermodynamic studies of oligodeoxyribonucleotides containing tandem lesions of thymidine glycol and 8-oxo-2'-deoxyguanosine.

Wang Yuesong Y Wang Yinsheng Y

Chemical research in toxicology 20060601 6

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 w ...[more]

PMID: 16780363

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Project description:Modified nucleotides often hinder and/or decrease the fidelity of DNA polymerases. Tandem lesions, which are comprised of DNA modifications at two contiguous nucleotide positions, can be even more detrimental to genome stability. Recently, tandem lesions containing 5-formyl-2'-deoxyuridine (5fdU) flanked at the 5'-position by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo) or N-(2-deoxy-α,β-D-erythropentofuranosyl)-N-(2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy•dG) were discovered. We examined the replication of 5'- 8-OxodGuo-5fdU and 5'-Fapy•dG-5fdU tandem lesions in HEK 293T cells and several polymerase deficient variants by transfecting single-stranded vectors containing them. The local sequence of the tandem lesions encompasses the 273 codon of the p53 gene, a mutational hot-spot. The bypass efficiency and mutation spectra of the tandem lesions were compared to those of the isolated lesions. Replication of weakly mutagenic 5-fdU is little changed when part of the 5'- 8-OxodGuo-5fdU tandem lesion. G → T transversions attributable to 8-OxodGuo increase > 10-fold when the tandem lesion is bypassed. 5'-Fapy•dG-5fdU has a synergistic effect on the error-prone bypass of both lesions. The mutation frequency (MF) of 5'-Fapy•dG-5fdU increases 3-fold compared to isolated Fapy•dG. In addition, a 5'-adjacent Fapy•dG significantly increases the MF of 5fdU. The major mutation, G → T transversions, decrease by almost a third in hPol κ- cells, which is the opposite effect when isolated Fapy•dG in the same sequence context is replicated in HEK 293T cells in the same sequence. Steady-state kinetics indicate that hPol κ contributes to greater G → T transversions by decreasing the specificity constant for dCTP compared to an isolated Fapy•dG. The greater conformational freedom of Fapy•dG compared to 8-OxodGuo and its unusual ability to epimerize at the anomeric center is believed to be the source of the complex effects of 5'-Fapy•dG-5fdU on replication.

Dataset Information

Synthesis and thermodynamic studies of oligodeoxyribonucleotides containing tandem lesions of thymidine glycol and 8-oxo-2'-deoxyguanosine.

Publications

Synthesis and thermodynamic studies of oligodeoxyribonucleotides containing tandem lesions of thymidine glycol and 8-oxo-2'-deoxyguanosine.

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