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DNA damage and interstrand cross-link formation upon irradiation of aryl iodide C-nucleotide analogues.

ABSTRACT: The 5-halopyrimidine nucleotides damage DNA upon UV-irradiation or exposure to gamma-radiolysis via the formation of the 2'-deoxyuridin-5-yl sigma-radical. The bromo and iodo derivatives of these molecules are useful tools for probing DNA structure and as therapeutically useful radiosensitizing agents. A series of aryl iodide C-nucleotides were incorporated into synthetic oligonucleotides and exposed to UV-irradiation and gamma-radiolysis. The strand damage produced upon irradiation of DNA containing these molecules is consistent with the generation of highly reactive sigma-radicals. Direct stand breaks and alkali-labile lesions are formed at the nucleotide analogue and flanking nucleotides. The distribution of lesion type and location varies depending upon the position of the aryl ring that is iodinated. Unlike 5-halopyrimidine nucleotides, the aryl iodides produce interstrand cross-links in duplex regions of DNA when exposed to gamma-radiolysis or UV-irradiation. Quenching studies suggest that cross-links are produced by gamma-radiolysis via capture of a solvated electron, and subsequent fragmentation to the sigma-radical. These observations suggest that aryl iodide C-nucleotide analogues may be useful as probes for excess electron transfer and radiosensitizing agents.

SUBMITTER: Ding H

PROVIDER: S-EPMC2813935 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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DNA damage and interstrand cross-link formation upon irradiation of aryl iodide C-nucleotide analogues.

Ding Hui H Greenberg Marc M MM

The Journal of organic chemistry 20100201 3

The 5-halopyrimidine nucleotides damage DNA upon UV-irradiation or exposure to gamma-radiolysis via the formation of the 2'-deoxyuridin-5-yl sigma-radical. The bromo and iodo derivatives of these molecules are useful tools for probing DNA structure and as therapeutically useful radiosensitizing agents. A series of aryl iodide C-nucleotides were incorporated into synthetic oligonucleotides and exposed to UV-irradiation and gamma-radiolysis. The strand damage produced upon irradiation of DNA conta ...[more]

PMID: 20067226

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Project description:DNA interstrand cross-links have important biological consequences and are useful biotechnology tools. Phenylselenyl substituted derivatives of thymidine (1) and 5-methyl-2'-deoxycytidine (5) produce interstrand cross-links in duplex DNA when oxidized by NaIO4. The mechanism involves a [2,3]-sigmatropic rearrangement of the respective selenoxides to the corresponding methide type intermediates, which ultimately produce the interstrand cross-links. Determination of the rate constants for the selenoxide rearrangements indicates that the rate-determining step for cross-linking is after methide formation. Cross-linking by the thymidine derivative in duplex DNA shows a modest kinetic preference when flanked by pyrimidines as opposed to purines. In contrast, the rate constant for cross-link formation from 5 opposite dG in duplex DNA is strongly dependent upon the flanking sequence and, in general, is at least an order of magnitude slower than that for 1 in an otherwise identical sequence. Introduction of mispairs at the base pairs flanking 5 or substitution of the opposing dG by dI significantly increases the rate constant and yield for cross-linking, indicating that stronger hydrogen bonding between the methide derived from it and dG compared to dA and the respective electrophile derived from 1 limits reaction by increasing the barrier to rotation into the required syn-conformation. Incorporation of 1 or 5 in triplex forming oligonucleotides (TFOs) that utilize Hoogsteen base pairing also yields interstrand cross-links. The dC derivative produces ICLs approximately 10x faster than the thymidine derivative when incorporated at the 5'-termini of the TFOs and higher yields when incorporated at internal sites. The slower, less efficient ICL formation emanating from 1 is attributed to reaction at N1-dA, which requires local melting of the duplex. In contrast, 5 produces cross-links by reacting with N7-dG. The cross-linking reactions of 1 and 5 illustrate the versatility and utility of these molecules as mechanistic probes and tools for biotechnology.

Dataset Information

DNA damage and interstrand cross-link formation upon irradiation of aryl iodide C-nucleotide analogues.

Publications

DNA damage and interstrand cross-link formation upon irradiation of aryl iodide C-nucleotide analogues.

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