Introduction and Perspectives on the Chemistry and Biology of DNA Damage

Geacintov, Nicholas E.; Broyde, Suse

doi:10.1002/9783527630110.ch1

Cited by 29 publications

(48 citation statements)

References 100 publications

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“…113,114 Collectively, these publications represent a rich source of information on the conformational features of structurally diverse forms of bulky DNA adducts for studying the relationships between their properties and their impact on biological phenomena. 115 …”

Section: Structural Features Of Bulky Pah–dna Adductsmentioning

confidence: 99%

Repair-Resistant DNA Lesions

Geacintov

Broyde

2017

Chem. Res. Toxicol.

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The eukaryotic global genomic nucleotide excision repair (GG-NER) pathway is the major mechanism that removes most bulky and some nonbulky lesions from cellular DNA. There is growing evidence that certain DNA lesions are repaired slowly or are entirely resistant to repair in cells, tissues, and in cell extract model assay systems. It is well established that the eukaryotic DNA lesion-sensing proteins do not detect the damaged nucleotide, but recognize the distortions/destabilizations in the native DNA structure caused by the damaged nucleotides. In this article, the nature of the structural features of certain bulky DNA lesions that render them resistant to NER, or cause them to be repaired slowly, is compared to that of those that are good-to-excellent NER substrates. Understanding the structural features that distinguish NER-resistant DNA lesions from good NER substrates may be useful for interpreting the biological significance of biomarkers of exposure of human populations to genotoxic environmental chemicals. NER-resistant lesions can survive to replication and cause mutations that can initiate cancer and other diseases. Furthermore, NER diminishes the efficacy of certain chemotherapeutic drugs, and the design of more potent pharmaceuticals that resist repair can be advanced through a better understanding of the structural properties of DNA lesions that engender repair-resistance.

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Section: Structural Features Of Bulky Pah–dna Adductsmentioning

confidence: 99%

Repair-Resistant DNA Lesions

Geacintov

Broyde

2017

Chem. Res. Toxicol.

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“…52,61 Depending on molecular size and shape of specific types of DNA lesions and the extent of helix distortion associated with their formation, they can be removed by one or more mechanism. 52,56 …”

Section: Discussionmentioning

confidence: 99%

Base Excision Repair of N⁶-Deoxyadenosine Adducts of 1,3-Butadiene

Wickramaratne

Banda

et al. 2016

Biochemistry

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The important industrial and environmental carcinogen, 1,3-butadiene (BD), forms a range of adenine adducts in DNA, including N6-(2-hydroxy-3-buten-1-yl)-2′-deoxyadenosine (N6-HB-dA), 1,N6-(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2′-deoxyadenosine (1,N6-HMHP-dA), and N6,N6-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (N6,N6-DHB-dA). If not removed prior to DNA replication, these lesions can contribute to A → T and A → G mutations commonly observed following exposure to BD and its metabolites. In the present study, base excision repair of BD-induced 2′-deoxyadenosine (BD-dA) lesions was investigated. Synthetic DNA duplexes containing site- and stereospecific S-N6-HB-dA, R,S-1,N6-HMHP-dA, and R,R-N6,N6-DHB-dA adducts were prepared by a post-oligomerization strategy. Incision assays with nuclear extracts from human fibrosarcoma (HT1080) cells have revealed that BD-dA adducts were recognized and cleaved by a BER mechanism, with relative excision efficiency in the order: S-N6-HB-dA > R,R-N6,N6-DHB-dA > R,S-1,N6-HMHP-dA. Strand cleavage at the adduct site was decreased in the presence of BER inhibitor methoxyamine and by competitor duplexes containing known BER substrates. Similar strand cleavage assays conducted using several eukaryotic DNA glycosylases/lyases [AAG, Mutyh, hNEIL1, and hOGG1] have failed to observe correct incision products at the BD-dA lesion sites, suggesting that a different BER enzyme may be involved in the removal of BD-dA adducts in human cells.

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“…The resulting structurally altered nucleobases can be misread by DNA polymerases, leading to heritable mutations and cancer (Geacintov and Broyde, S.2010). A complex mixture of DNA lesions can be formed following exposure, making it difficult to attribute the observed biological effects to specific type of carcinogen-DNA adducts.…”

Section: Commentarymentioning

confidence: 99%

Synthesis of DNA Oligodeoxynucleotides Containing Site‐Specific 1,3‐Butadiene‐ Deoxyadenosine Lesions

Wickramaratne

Seiler

Tretyakova

2015

CP Nucleic Acid Chemistry

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Post-oligomerization synthesis is a useful technique for preparing site-specifically modified DNA oligomers. This approach involves site-specific incorporation of inherently reactive halogenated nucleobases into DNA strands using standard solid phase synthesis, followed by post-oligomerization nucleophilic aromatic substitution (SNAr) reactions with carcinogen-derived synthons. In these reactions, the inherent reactivities of DNA and carcinogen-derived species are reversed: the modified DNA nucleobase acts as an electrophile, while the carcinogen-derived species acts as a nucleophile. In the present protocol, we describe the use of the post-oligomerization approach to prepare DNA strands containing site- and stereospecific N6-adenine and N1, N6-adenine adducts induced by epoxide metabolites of the known human and animal carcinogen, 1,3-butadiene (BD). The resulting oligomers containing site specific, structurally defined DNA adducts can be used in structural and biological studies to reveal the roles of specific BD adducts in carcinogenesis and mutagenesis.

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Introduction and Perspectives on the Chemistry and Biology of DNA Damage

Cited by 29 publications

References 100 publications

Repair-Resistant DNA Lesions

Repair-Resistant DNA Lesions

Base Excision Repair of N⁶-Deoxyadenosine Adducts of 1,3-Butadiene

Synthesis of DNA Oligodeoxynucleotides Containing Site‐Specific 1,3‐Butadiene‐ Deoxyadenosine Lesions

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Introduction and Perspectives on the Chemistry and Biology of DNA Damage

Cited by 29 publications

References 100 publications

Repair-Resistant DNA Lesions

Repair-Resistant DNA Lesions

Base Excision Repair of N6-Deoxyadenosine Adducts of 1,3-Butadiene

Synthesis of DNA Oligodeoxynucleotides Containing Site‐Specific 1,3‐Butadiene‐ Deoxyadenosine Lesions

Contact Info

Product

Resources

About

Base Excision Repair of N⁶-Deoxyadenosine Adducts of 1,3-Butadiene