Excision of Environmental Carcinogen-DNA Lesions by Human NER enzymes

人类 NER 酶切除环境致癌物 DNA 损伤

• 批准号: 8206817
• 负责人: Nicholas E Geacintov
• 金额: $ 31.77万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206817
• 关键词: 4-biphenylamine; Adenine; Adopted; Affect; Air Pollutants; Animals; Aromatic Amines; Aromatic Polycyclic Hydrocarbons; Base Sequence; Bay Region; Benzo(a)pyrene; Binding; Biological Markers; Biological Models; Breathing; Bypass; Cancer Etiology; Carcinogens; Cations; Cells; Characteristics; Chemical Structure; Chemicals; Coal; Complex; Cytochrome P450; DNA; DNA Adducts; DNA Damage; DNA Repair; DNA biosynthesis; DNA lesion; Defense Mechanisms; Development; Disease; Distant; Elderly; Environment; Environmental Carcinogens; Epoxy Compounds; Etiology; Excision; Exposure to; Family; Fishes; Food; Fossil Fuels; Free Radicals; Genetic Polymorphism; Glycols; Guanine; Health; Heating; Human; Human body; Hydrogen Bonding; Individual; Ingestion; Investigation; Lead; Lesion; Life; Malignant Neoplasms; Meat; Mediating; Metabolic Activation; Methods; Modeling; Molecular; Molecular Conformation; Monitor; Mutagens; Mutation; Nucleotide Excision Repair; Outcome; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Pattern; Play; Population; Positioning Attribute; Predisposition; Problem Solving; Process; Progress Reports; Property; Proteins; Protocols documentation; Pyrenes; Reaction; Reporting; Research Project Grants; Resistance; Risk; Role; Side; Site; Staging; Structure; Thermodynamics; Tobacco smoke; Variant; World Health Organization; adduct; amino group; base; benzo(a)pyrene-DNA adduct; carcinogenesis; cigarette smoking; cooking; design; ds-DNA; enantiomer; environment related cancer; exposed human population; hazard; heterocyclic aromatic amines; human DNA damage; insight; nucleobase; oxidation; oxidative DNA damage; prevent; pyridine; repair enzyme; repaired; research study; response; success; tool; working group

It is evident from many different experiments, that the human nucleotide excision repair (NER) apparatus first distinguishes structural DNA perturbations caused by bulky lesions derived from the reactions of metabolically activated environmental carcinogens that enter the human body. This step entails the formation of XPC/HR23B complexes that partially open the duplex near the lesion site. The initial structural distortions caused by the lesions and the subsequent strand separation suggest that base-base stacking and hydrogen bonding interactions are first weakened and then broken during these initial phenomena. In this project, we will examine the effects of structurally different lesions of different adduct conformations on these initial structural distortions, and then use variations in base sequence context as a tool to modulate these base stacking interactions and thus gain insight into the specific structural factors that affect human NER activity. In Specific Aim 1, the Structural basis of recognition and processing of DNA damage by the human NER apparatus will be investigated. This aim will be focused on DNA lesions of different chemical structure, physical size, and conformational properties positioned at the same site in otherwise completely identical sequence contexts. In Specific Aim 2, the local DNA distortions caused by the lesions will be modulated by varying the base sequence context in which the lesions are embedded, and determine effects of different flanking bases on the structural characteristics and changes in NER activity. In Specific aim 3, the effects of adduct structure and base sequence on binding and patterns of helix opening by the human NER lesion-recognizing XPC/HR23B heterodimer duplex will be investigated. The results of this project will have ultimate translational identification by providing new information about DNA lesiosn that are resistant to DNA repair, thus providing important information about biomarkers of exposure of the human population to environmental carcinogens.

从许多不同的实验中可以明显看出，人核苷酸切除修复（NER）设备 首先区分由源自源自反应的笨重病变引起的结构DNA扰动 进入人体的代谢活化的环境致癌物。此步骤需要编队 XPC/HR23B复合物的部分，该复合物部分打开病变部位附近的双链体。最初的结构扭曲 由病变和随后的链分离引起 在这些初始现象期间，粘结相互作用首先被削弱，然后破裂。在这个项目中，我们将 检查不同加合物构象的结构不同病变对这些初始结构的影响 扭曲，然后使用基本序列上下文中的变体作为调节这些基础堆叠的工具 相互作用，从而深入了解影响人类活性的特定结构因素。具体 AIM 1，人类NER设备对DNA损害的识别和处理的结构基础将是 调查。该目标将集中于不同化学结构，物理大小和的DNA病变 构象性质位于同一位点，在其他完全相同的序列上下文中。在 特定的目标2，由病变引起的局部DNA畸变将通过改变碱而调节 嵌入病变的序列上下文，并确定不同侧翼碱基对 结构特征和NER活性的变化。在特定的目标3中，加合物结构和 人类病变 - 识别XPC/HR23B的结合和螺旋开口的基础序列 杂化双链体将进行研究。该项目的结果将具有最终的翻译标识 通过提供有关DNA Lesiosn耐DNA修复的新信息，从而提供了重要 有关人口暴露于环境致癌物的生物标志物的信息。

项目成果

Nucleotide selectivity opposite a benzo[a]pyrene-derived N2-dG adduct in a Y-family DNA polymerase: a 5'-slippage mechanism.

Y 家族 DNA 聚合酶中与苯并[a]芘衍生的 N2-dG 加合物相反的核苷酸选择性：5-滑移机制。

• DOI: 10.1021/bi701839q
• 发表时间: 2008
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Xu,Pingna;Oum,Lida;Geacintov,NicholasE;Broyde,Suse
• 通讯作者: Broyde,Suse

DNA polymerase zeta cooperates with polymerases kappa and iota in translesion DNA synthesis across pyrimidine photodimers in cells from XPV patients.

DNA 聚合酶 zeta 与聚合酶 kappa 和 iota 合作，在 XPV 患者细胞中跨嘧啶光二聚体进行跨损伤 DNA 合成。

• 发表时间: 2009
• 期刊: Proc.Natl.Acad.Sci.USA 106
• 作者: Ziv O;Geacintov;N.Nakajima;S;Yasui;A.Livneh;Z.
• 通讯作者: Z.

Dnmt3a-CD is less susceptible to bulky benzo[a]pyrene diol epoxide-derived DNA lesions than prokaryotic DNA methyltransferases.

• DOI: 10.1021/bi101717b
• 发表时间: 2011-02-08
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Lukashevich OV;Baskunov VB;Darii MV;Kolbanovskiy A;Baykov AA;Gromova ES
• 通讯作者: Gromova ES

DNA damage bypass operates in the S and G2 phases of the cell cycle and exhibits differential mutagenicity.

• DOI: 10.1093/nar/gkr596
• 发表时间: 2012-01
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Diamant N;Hendel A;Vered I;Carell T;Reissner T;de Wind N;Geacinov N;Livneh Z
• 通讯作者: Livneh Z

PCNA ubiquitination is important, but not essential for translesion DNA synthesis in mammalian cells.

• DOI: 10.1371/journal.pgen.1002262
• 发表时间: 2011-09
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Hendel A;Krijger PH;Diamant N;Goren Z;Langerak P;Kim J;Reissner T;Lee KY;Geacintov NE;Carell T;Myung K;Tateishi S;D'Andrea A;Jacobs H;Livneh Z
• 通讯作者: Livneh Z