DNA BASE SEQUENCE EFFECTS IN CHEMICAL CARCINOGENESIS

DNA 碱基序列在化学致癌作用中的作用

• 批准号: 6475917
• 负责人: Nicholas E Geacintov
• 金额: $ 23.13万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6475917
• 关键词: DNA directed DNA polymerase; DNA repair; DNA replication; adduct; benzopyrenediol epoxide; chemical carcinogenesis; enzyme activity; gel electrophoresis; high performance liquid chromatography; neoplasm /cancer genetics; nucleic acid sequence; point mutation

DESCRIPTION: The major hypothesis to be tested in this application is that the conformational and functional properties of site-specifically modified DNA sequences with single, stereochemical defined benzopyrene diolepoxide (BPDE)-deoxyguanosine, BPDE-deoxyadenosine, and deoxyadenosine adducts derived from the fjord region anti-benzo(c)phenathrene-3,4-diol-1,2-epoxide, depend on the bases flanking the lesions. This hypothesis will be tested by 1) determining the effects of base sequence on the conformational characteristics of structurally and stereochemical defined adducts, 2) investigating the structural characteristics that are critical to the interactions with and excision of these lesions, positioned in different base sequence contexts, by nucleotide excision repair enzymes in vitro, and 3) investigating the effects of base sequence on the mutation prone processing of these adducts by DNA polymerases in vitro. A number of DNA adduct structures have already been established by NMR methods, thus providing a fertile basis for understanding structure biological activity relationships. These structurally characterized adducts will be selected for study, followed by studies of guanine-rich sequences that are known to be mutation hot spots in vivo, and by a systematic examination of the effects of the two bases flanking the lesions. The effects of base sequence on adduct induced bends and flexible hinge joints, direction of bending, and helix unwinding, will be examined using gel electrophoresis techniques. The principal investigator hypothesizes that base sequences leading to flexibility can affect the multiplicity of adduct conformations that can be assumed by the polycyclic residues at primer/template junctions in DNA replication enzyme complexes in vitro, thus influencing the mutagenic specificities of the adducts.

描述：本申请中待检验的主要假设是， 位点特异性修饰的蛋白质的构象和功能性质 具有单个立体化学定义的苯并芘二羟环氧化物的DNA序列 （BPDE）-脱氧鸟苷、BPDE-脱氧腺苷和脱氧腺苷加合物 衍生自峡湾地区反-苯并（c）菲-3，4-二醇-1，2-环氧化物， 取决于病变两侧的碱基 这一假设将由以下人员进行检验： 1)确定碱基序列对构象的影响， 结构和立体化学定义的加合物的特征，2） 研究对生物体结构至关重要的结构特征 相互作用和切除这些病变，定位在不同的 通过体外核苷酸切除修复酶， 3)研究碱基序列对突变倾向的影响， 这些加合物在体外由DNA聚合酶加工。 多个DNA 加合物结构已经通过NMR方法建立，因此 为理解结构和生物活性提供了丰富的基础 关系。 将选择这些具有结构特征的加合物 研究，其次是研究富含鸟嘌呤的序列， 是突变热点，并通过系统的检查， 病变两侧的两个碱基的影响。 碱基序列的影响 加合物诱导弯曲和柔性铰链接头，弯曲方向， 螺旋解旋，将使用凝胶电泳技术进行检查。 的 首席研究员假设，导致 柔性可以影响加合物构象的多样性， 假定在DNA中引物/模板连接处的多环残基 体外复制酶复合物，从而影响致突变性 加合物的特异性。

项目成果

Trapping of DNA nucleotide excision repair factors by nonrepairable carcinogen adducts.

不可修复的致癌物加合物捕获 DNA 核苷酸切除修复因子。

• 发表时间: 2002
• 期刊: Cancer research.
• 作者: Buterin,Tonko;Hess,MartinT;Gunz,Daniela;Geacintov,NicholasE;Mullenders,LeonH;Naegeli,Hanspeter
• 通讯作者: Naegeli,Hanspeter

Base sequence effects in bending induced by bulky carcinogen-DNA adducts: experimental and computational analysis.

大体积致癌物-DNA 加合物诱导弯曲的碱基序列效应：实验和计算分析。

• DOI: 10.1021/bi002643x
• 发表时间: 2001
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Ruan,Q;Zhuang,P;Li,S;Perlow,R;Srinivasan,AR;Lu,XJ;Broyde,S;Olson,WK;Geacintov,NE
• 通讯作者: Geacintov,NE

Role of base sequence context in conformational equilibria and nucleotide excision repair of benzo[a]pyrene diol epoxide-adenine adducts.

碱基序列背景在苯并[a]芘二醇环氧化物-腺嘌呤加合物的构象平衡和核苷酸切除修复中的作用。

• DOI: 10.1021/bi0270081
• 发表时间: 2003
• 期刊: Biochemistry.
• 作者: Yan,Shixiang;Wu,Min;Buterin,Tonko;Naegeli,Hanspeter;Geacintov,NicholasE;Broyde,Suse
• 通讯作者: Broyde,Suse

Influence of bulky polynuclear carcinogen lesions in a TATA promoter sequence on TATA binding protein-DNA complex formation.

TATA 启动子序列中大量多核致癌物损伤对 TATA 结合蛋白-DNA 复合物形成的影响。

• DOI: 10.1021/bi002543r
• 发表时间: 2001
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Rechkoblit,O;Krzeminsky,J;Amin,S;Jernström,B;Louneva,N;Geacintov,NE
• 通讯作者: Geacintov,NE

Base sequence dependence of in vitro translesional DNA replication past a bulky lesion catalyzed by the exo- Klenow fragment of Pol I.

体外跨损伤 DNA 复制经过大体积损伤的碱基序列依赖性，由 Pol I 的外切 Klenow 片段催化。

• DOI: 10.1021/bi010005o
• 发表时间: 2001
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Zhuang,P;Kolbanovskiy,A;Amin,S;Geacintov,NE
• 通讯作者: Geacintov,NE