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Radiosensitization by a modified nucleotide that produces DNA interstrand cross-links under hypoxic conditions.

ABSTRACT: This paper describes the reactivity of a molecule that combines two desirable chemical processes into one molecule for the first time. Interstrand cross-links (ISCs) are an effective family of lesions produced by cytotoxic agents that target DNA. For instance, ISCs are the source of mitomycin C's cytotoxicity. Radiosensitizing agents are molecules that enhance DNA damage produced by ionizing radiation, especially under O2-deficient conditions. Phenyl selenide 1 is the first example of a modified nucleotide that can be incorporated in DNA by polymerases, which produces ISCs when DNA containing it is exposed to gamma-radiolysis under O2-deficient conditions. These experiments suggest that 1 could be useful as a novel type of radiosensitizing agent.

SUBMITTER: Hong IS

PROVIDER: S-EPMC1414064 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Radiosensitization by a modified nucleotide that produces DNA interstrand cross-links under hypoxic conditions.

Hong In Seok IS Ding Hui H Greenberg Marc M MM

Journal of the American Chemical Society 20060201 7

This paper describes the reactivity of a molecule that combines two desirable chemical processes into one molecule for the first time. Interstrand cross-links (ISCs) are an effective family of lesions produced by cytotoxic agents that target DNA. For instance, ISCs are the source of mitomycin C's cytotoxicity. Radiosensitizing agents are molecules that enhance DNA damage produced by ionizing radiation, especially under O2-deficient conditions. Phenyl selenide 1 is the first example of a modified ...[more]

PMID: 16478174

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Project description:Bifunctional DNA alkylating agents form a diverse assortment of covalent DNA interstrand cross-linked (ICL) structures that are potent cytotoxins. Because it is implausible that cells could possess distinct DNA repair systems for each individual ICL, it is believed that common structural and dynamic features of ICL damage are recognized, rather than specific structural characteristics of each cross-linking agent. Investigation of the structural and dynamic properties of ICLs that might be important for recognition has been complicated by heterogeneous incorporation of these lesions into DNA. To address this problem, we have synthesized and characterized several homogeneous ICL DNAs containing site-specific staggered N4-cytosine-ethyl-N4-cytosine cross-links. Staggered cross-links were introduced in two ways, in a manner that preserves the overall structure of B-form duplex DNA and in a manner that highly distorts the DNA structure, with the goal of understanding how structural and dynamic properties of diverse ICL duplexes might flag these sites for repair. Measurements of base pair opening dynamics in the B-form ICL duplex by (1)H NMR line width or imino proton solvent exchange showed that the guanine base opposite the cross-linked cytosine opened at least 1 order of magnitude more slowly than when in a control matched normal duplex. To a lesser degree, the B-form ICL also induced a decrease in base pair opening dynamics that extended from the site of the cross-link to adjacent base pairs. In contrast, the non-B-form ICL showed extensive conformational dynamics at the site of the cross-link, which extended over the entire DNA sequence. Because DNA duplexes containing the B-form and non-B-form ICL cross-links have both been shown to be incised when incubated in mammalian whole cell extracts, while a matched normal duplex is not, we conclude that intrinsic DNA dynamics is not a requirement for specific damage incision of these ICLs. Instead, we propose a general model in which destabilized ICL duplexes serve to energetically facilitate binding of DNA repair factors that must induce bubbles or other distortions in the duplex. However, the essential requirement for incision is an immobile Y-junction where the repair factors are stably bound at the site of the ICL, and the two DNA strands are unpaired.

Dataset Information

Radiosensitization by a modified nucleotide that produces DNA interstrand cross-links under hypoxic conditions.

Publications

Radiosensitization by a modified nucleotide that produces DNA interstrand cross-links under hypoxic conditions.

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