DNA Adducts of Styrene and Other Vinyl Monomers

苯乙烯和其他乙烯基单体的 DNA 加合物

• 批准号: 8051694
• 负责人: Michael P Stone
• 金额: $ 36.41万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051694
• 关键词: 3,4-epoxy-1-butene; Alkylation; Amino Acids; Base Pairing; Binding; Biochemical; Biological; Biological Process; Breathing; Butadiene; Bypass; Cancer Etiology; Carcinogens; Chemistry; Chronic; Complex; Crystallization; Crystallography; DNA; DNA Adducts; DNA Alkylation; DNA Crosslinking; DNA Damage; DNA Sequence; DNA Structure; Deamination; Deoxyadenosines; Deoxyuridine; Divalent Cations; Enzymes; Epoxy Compounds; Etiology; Exposure to; FAPy; Face; Family; Glycols; Human; Hydrogen Bonding; Induced Mutation; Investigation; Kinetics; Lesion; Major Groove; Malignant Neoplasms; Mediating; Modeling; Molecular Conformation; Monitor; Mono-S; Mutagenesis; Mutation; Nature; Nucleotides; Occupational Exposure; Outcome; Plastics; Polymerase; Production; Residual state; Risk; Role; Rotation; Rubber; Sampling; Site-Directed Mutagenesis; Structure; Structure-Activity Relationship; Sulfolobus solfataricus; Synchrotrons; adduct; anomer; base; crosslink; deoxyinosine; erythritol anhydride; genotoxicity; hydroxyl group; insight; leukemia; medical schools; monomer; next generation; professor; stereochemistry

DESCRIPTION (provided by applicant): Styrene and butadiene, used in the production of rubber and plastics, are implicated in the etiology of human cancer. Butadiene is classified by the USEPA as "carcinogenic to humans by inhalation", by the NTP as a "known human carcinogen". Chronic occupational exposures to mixtures of styrene and butadiene correlate with risk for leukemias. This project will examine the etiology of butadiene-induced mutagenesis, developing structure-activity relationships for DNA adducts arising from butadiene epoxides and associated with human genotoxicity. The first aim will combine NMR, crystallography, and biochemical approaches to examine N1- deoxyinosine adducts arising from deamination of N1-deoxyadenosine alkylation products. We propose a role for Y-family Pol i utilizing the Hoogsteen face of dl for templating, allowing incorporation of protonated dCTP or dATP. The second aim will employ NMR and crystallographic approaches to examine stereoisomeric N3-dU adducts of butadiene monoepoxide, which arise from deamination of N3-dC adducts. We propose that they do not undergo rotation about the glycosyl bond, into the syn conformation, thus leading to fundamentally different biological and mutagenic outcomes. The third aim will use NMR, biochemical, and site-specific mutagenesis to examine N7-dG adducts arising from exposures to butadiene epoxides. Emphasis will be placed on relationships of N7-dG adduction to the formation of interstrand and intrastrand crosslinks by butadiene diepoxide; this depends upon DNA sequence and diepoxide stereochemistry. Interstrand crosslinks form in 5'-GNC-3' sequences. We propose that the orientations of N7-dG butadiene diol epoxide mono-adducts depend upon stereochemistry, differentially orienting the diol epoxides for interstrand vs. intrastrand crosslinking. The chemistry, mutational spectra, and replication bypass of N7-dG FAPy re-arrangement products will be examined. Overall, we will delineate mechanism(s) by which N1-dl and N3-dU butadiene adducts induce mutations, and why specific polymerase(s) mediate lesion bypass. Insight will be gained into DNA crosslinking chemistry of butadiene diepoxides. Insight will be gained into the chemistry of butadiene N7-dG FAPy lesions, their biological processing, and their structures. This is essential to understanding how occupational exposures to mixtures of styrene and butadiene contribute to human genotoxicity and cancer etiology.

描述（由申请人提供）：用于生产橡胶和塑料的苯乙烯和丁二烯与人类癌症的病因有关。丁二烯被USEPA分类为“通过吸入对人类的致癌”，由NTP归类为“已知人类致癌物”。长期对苯乙烯和丁二烯混合物的职业暴露与白血病风险相关。该项目将检查丁二烯诱导的诱变的病因，发展由丁二烯环氧化物引起的DNA加合物的结构活性关系，并与人类遗传毒性相关。第一个目的将结合NMR，晶体学和生化方法，以检查N1-脱氧腺苷烷基化产物脱氨酸引起的N1-脱氧加合物。我们提出了使用DL的Hoogsteen脸进行模板的Y-家庭pol的作用，允许掺入质子化的DCTP或DATP。第二个目的将采用NMR和晶体学方法来检查丁二烯单氧化丁烷的立体体N3-DU加合物，这是由N3-DC加合物的脱氨酸引起的。我们建议它们不会围绕糖基键旋转，从而进入Syn构象，从而导致根本不同的生物学和诱变结果。第三个目标将使用NMR，生化和位点特异性诱变来检查由丁二烯环氧化物暴露引起的N7-DG加合物。将重点放在丁二烯二氧化物的N7-DG内收于链间和astrand交联的形成上的关系。这取决于DNA序列和二氧化物立体化学。 5'-gnc-3'序列中的链间交联。我们建议N7-DG丁二烯二醇单氧化物单元的方向取决于立体化学，从而差异化了二醇环氧化物的二醇氧化物，以进行链链与astrand河流交联。将检查N7-DG Fapy再进行重新排序产物的化学，突变光谱和复制旁路。总体而言，我们将描述N1-DL和N3-DU丁二烯加合物诱导突变的机制，以及为什么特定的聚合酶介导了病变旁路。洞察力将获得丁二烯二氧化物的DNA交联化学。洞察力将获得丁二烯N7-DG FAPY病变的化学，其生物加工及其结构。这对于了解如何对苯乙烯和丁二烯混合物的职业暴露有助于人类遗传毒性和癌症病因至关重要。

项目成果

Structure of an oligodeoxynucleotide containing a butadiene oxide-derived N1 beta-hydroxyalkyl deoxyinosine adduct in the human N-ras codon 61 sequence.

含有人 N-ras 密码子 61 序列中丁二烯氧化物衍生的 N1 β-羟烷基脱氧肌苷加合物的寡脱氧核苷酸的结构。

• DOI: 10.1021/bi0482452
• 发表时间: 2005
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Scholdberg,TandaceA;Merritt,WKeither;Dean,StephenM;Kowalcyzk,Agnieska;Harris,ConstanceM;Harris,ThomasM;Rizzo,CarmeloJ;Lloyd,RStephen;Stone,MichaelP
• 通讯作者: Stone,MichaelP

Major groove orientation of the (2S)-N(6)-(2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine DNA adduct induced by 1,2-epoxy-3-butene.

1,2-环氧-3-丁烯诱导的 (2S)-N(6)-(2-羟基-3-丁烯-1-基)-2'-脱氧腺苷 DNA 加合物的主沟方向。

• DOI: 10.1021/tx500159w
• 发表时间: 2014-10-20
• 期刊: CHEMICAL RESEARCH IN TOXICOLOGY
• 影响因子: 4.1
• 作者: Kowal, Ewa A.;Wickramaratne, Susith;Kotapati, Srikanth;Turo, Michael;Tretyakova, Natalia;Stone, Michael P.
• 通讯作者: Stone, Michael P.

Mispairing of a site specific major groove (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl DNA Adduct of butadiene diol epoxide with deoxyguanosine: formation of a dA(anti).dG(anti) pairing interaction.

位点特异性主沟 (2S,3S)-N6-(2,3,4-三羟基丁基)-2-脱氧腺苷 DNA 加合物丁二烯二醇环氧化物与脱氧鸟苷的错配：形成 dA(抗).dG(抗)

• DOI: 10.1021/tx049772p
• 发表时间: 2005
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Scholdberg,TandaceA;Nechev,LubomirV;Merritt,WKeither;Harris,ThomasM;Harris,ConstanceM;Lloyd,RStephen;Stone,MichaelP
• 通讯作者: Stone,MichaelP

Sequence- and stereospecific conformational rearrangement of styrene oxide adducts located at A x C mismatched base pairs.

位于 A x C 不匹配碱基对处的氧化苯乙烯加合物的序列和立体特异性构象重排。

• DOI: 10.1021/bi992080t
• 发表时间: 2000
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Simeonov,MF;Tamura,PJ;Wilkinson,AS;Harris,CM;Harris,TM;Stone,MP
• 通讯作者: Stone,MP

Structure of a site specific major groove (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl DNA adduct of butadiene diol epoxide.

丁二烯二醇环氧化物的位点特异性主沟 (2S,3S)-N6-(2,3,4-三羟基丁基)-2-脱氧腺苷 DNA 加合物的结构。

• DOI: 10.1021/tx034271
• 发表时间: 2004
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Scholdberg,TandaceA;Nechev,LubomirV;Merritt,WKeither;Harris,ThomasM;Harris,ConstanceM;Lloyd,RStephen;Stone,MichaelP
• 通讯作者: Stone,MichaelP