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Nucleotide excision repair efficiencies of bulky carcinogen-DNA adducts are governed by a balance between stabilizing and destabilizing interactions.

ABSTRACT: The nucleotide excision repair (NER) machinery, the primary defense against cancer-causing bulky DNA lesions, is surprisingly inefficient in recognizing certain mutagenic DNA adducts and other forms of DNA damage. However, the biochemical basis of resistance to repair remains poorly understood. To address this problem, we have investigated a series of intercalated DNA-adenine lesions derived from carcinogenic polycyclic aromatic hydrocarbon (PAH) diol epoxide metabolites that differ in their response to the mammalian NER apparatus. These stereoisomeric PAH-derived adenine lesions represent ideal model systems for elucidating the effects of structural, dynamic, and thermodynamic properties that determine the recognition of these bulky DNA lesions by NER factors. The objective of this work was to gain a systematic understanding of the relation between aromatic ring topology and adduct stereochemistry with existing experimental NER efficiencies and known thermodynamic stabilities of the damaged DNA duplexes. For this purpose, we performed 100 ns molecular dynamics studies of the lesions embedded in identical double-stranded 11-mer sequences. Our studies show that, depending on topology and stereochemistry, stabilizing PAH-DNA base van der Waals stacking interactions can compensate for destabilizing distortions caused by these lesions that can, in turn, cause resistance to NER. The results suggest that the balance between helix stabilizing and destabilizing interactions between the adduct and nearby DNA residues can account for the variability of NER efficiencies observed in this class of PAH-DNA lesions.

SUBMITTER: Cai Y

PROVIDER: S-EPMC3292408 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Nucleotide excision repair efficiencies of bulky carcinogen-DNA adducts are governed by a balance between stabilizing and destabilizing interactions.

Cai Yuqin Y Geacintov Nicholas E NE Broyde Suse S

Biochemistry 20120209 7

The nucleotide excision repair (NER) machinery, the primary defense against cancer-causing bulky DNA lesions, is surprisingly inefficient in recognizing certain mutagenic DNA adducts and other forms of DNA damage. However, the biochemical basis of resistance to repair remains poorly understood. To address this problem, we have investigated a series of intercalated DNA-adenine lesions derived from carcinogenic polycyclic aromatic hydrocarbon (PAH) diol epoxide metabolites that differ in their res ...[more]

PMID: 22242833

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Project description:The nucleotide excision repair of certain bulky DNA lesions is abrogated in some specific non-canonical DNA base sequence contexts, while the removal of the same lesions by the nucleotide excision repair mechanism is efficient in duplexes in which all base pairs are complementary. Here we show that the nucleotide excision repair activity in human cell extracts is moderate-to-high in the case of two stereoisomeric DNA lesions derived from the pro-carcinogen benzo[a]pyrene (cis- and trans-B[a]P-N2-dG adducts) in a normal DNA duplex. By contrast, the nucleotide excision repair activity is completely abrogated when the canonical cytosine base opposite the B[a]P-dG adducts is replaced by an abasic site in duplex DNA. However, base excision repair of the abasic site persists. In order to understand the structural origins of these striking phenomena, we used NMR and molecular spectroscopy techniques to evaluate the conformational features of 11mer DNA duplexes containing these B[a]P-dG lesions opposite abasic sites. Our results show that in these duplexes containing the clustered lesions, both B[a]P-dG adducts adopt base-displaced intercalated conformations, with the B[a]P aromatic rings intercalated into the DNA helix. To explain the persistence of base excision repair in the face of the opposed bulky B[a]P ring system, molecular modeling results suggest how the APE1 base excision repair endonuclease, that excises abasic lesions, can bind productively even with the trans-B[a]P-dG positioned opposite the abasic site. We hypothesize that the nucleotide excision repair resistance is fostered by local B[a]P residue-DNA base stacking interactions at the abasic sites, that are facilitated by the absence of the cytosine partner base in the complementary strand. More broadly, this study sets the stage for elucidating the interplay between base excision and nucleotide excision repair in processing different types of clustered DNA lesions that are substrates of nucleotide excision repair or base excision repair mechanisms.

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Dataset Information

Nucleotide excision repair efficiencies of bulky carcinogen-DNA adducts are governed by a balance between stabilizing and destabilizing interactions.

Publications

Nucleotide excision repair efficiencies of bulky carcinogen-DNA adducts are governed by a balance between stabilizing and destabilizing interactions.

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