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Mutational spectra of bulky DNA lesions

大体积 DNA 损伤的突变谱

基本信息

批准号：
10312790
负责人：
Deyu Li
金额：
$ 36.01万
依托单位：
UNIVERSITY OF RHODE ISLAND
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312790
关键词：
Area Aromatic Amines Basic Science Biological Markers Biomimetics Bypass Carbolines Carcinogens Cells Cellular Assay Chemicals Clinical DNA Adducts DNA Damage DNA lesion Development Disease Education Environment Epigenetic Process Escherichia coli Event Frequencies Genes Genetic Genome Goals Human Individual Institutes Intervention Laboratories Lesion Location Mammalian Cell Massachusetts Methods Molecular Mutation Mutation Spectra Nucleotides Oligonucleotides Pattern Plasmids Polymerase Positioning Attribute Research Research Personnel Scientist Site Symptoms System Technology Testing Toxic Environmental Substances Toxin Training Universities Walkers Work adduct authority base biological systems chemical synthesis diphenyl early onset environmental toxicology experimental study genome integrity genomic biomarker insight repaired student mentoring tool translational therapeutics tumor

项目摘要

Many environmental toxins damage DNA and cause diseases. The exposure of cells with DNA damaging agents results in the formation of a host of different DNA lesions, a subset of which can give rise to mutations. If one were to plot the frequency and type of mutation as a function of the position along a gene, a distribution is generated that is commonly referred to as a mutational spectrum. Mutational spectra are usually happened by sites at which mutagenic events occur more frequently than expected. These are mutational hotspots and the formation of hotspots can arise from three scenarios: formation, repair and replication. It is reasonable to speculate that these events are modulated by the local sequence environment surrounding the base to be modified, or the DNA lesion to be repaired or replicated. It is important for environmental scientists to provide insights into the evolutionary changes that foreshadow tumor development before overt clinical symptoms appear. This goal is crucial because some diseases, such as tumors, show few clinical symptoms until the disease has reached a late, usually fatal stage. Early onset genomic biomarkers might enable intervention to eliminate or curtail development of the disease. The biomarkers of a disease caused by a specific toxin can be obtained by studying the mutational spectra of DNA lesions generated from the toxin. Experimental studies of the mutations and mutation spectra induced by environmental toxins have traditionally focused on single mutations. However, the origins of mutational hotspots is complicated by the neighboring contexts. The selective formation, replication, and repair of a DNA lesion can, in principle, be influenced by the surrounding nucleotide environment from both 5’ and 3’ ends. A nearest-neighbor analysis of a certain DNA lesion (NXN, X = lesion, N = one of the four nucleotides) will provide a structural rationale for mutational spectra in environmental toxin related human tumors. In this proposal, we will study individual lesions of environmental toxins under all the genetic and epigenetic relevant contexts. In this project, we select two important environmental toxins, 4-amino biphenyl (ABP) and amino alpha carboline (AaC) to study the mutational spectra of their major DNA lesions and correlate with mutational signatures of diseases caused by them. The central hypothesis of this project is that DNA lesions generated by environmental toxins will cause different mutational spectra in a sequence dependent manner. The Specific Aims are: Specific Aim 1: Chemical synthesis and identification of bulky DNA adduct containing oligonucleotides. Specific Aim 2: Mutational spectra of bulky lesions in cell. Specific Aim 3: Replication bypass of lesions by translesion synthesis polymerases. At the conclusion of this project we will have demonstrated how the interaction between environmental toxins and mutational spectra. These studies shall utilize in a combination of genetic, chemical, and spectroscopic tools to understand and manipulate biological systems at the molecular level.

许多环境毒素会破坏DNA并导致疾病。将细胞暴露于DNA破坏剂导致形成一系列不同的DNA损伤，其中一部分可以引起突变。如果一个如果将突变的频率和类型绘制成基因沿着位置的函数，则分布为通常被称为突变谱。突变谱通常是由诱变事件发生频率高于预期的位点。这些是突变热点，热点的形成可以由三种情况引起：形成、修复和复制。是合理的推测这些事件是由碱基周围的局部序列环境调制的，修改，或DNA损伤修复或复制。环境科学家必须提供深入了解在出现明显临床症状之前预示肿瘤发展的进化变化出现这一目标是至关重要的，因为一些疾病，如肿瘤，显示很少的临床症状，直到治疗结束。疾病已经到了晚期，通常是致命的阶段。早期发病的基因组生物标志物可能有助于干预，消除或减少疾病的发展。由特定毒素引起的疾病的生物标志物可以是通过研究毒素产生的DNA损伤的突变谱获得。的实验研究由环境毒素引起的突变和突变谱传统上集中在单个突变。然而，突变热点的起源是复杂的相邻上下文。选择性原则上，DNA损伤的形成、复制和修复可以受到周围核苷酸的影响。从5'端和3'端的环境。某个DNA损伤的最近邻分析（NXN，X =损伤，N =四种核苷酸中的一种）将为环境毒素中的突变谱提供结构上的基本原理与人类肿瘤有关。在本提案中，我们将研究环境毒素在所有条件下的个体病变。遗传和表观遗传相关背景。本课题选择了两种重要的环境毒素4-氨基联苯（ABP）和氨基α咔啉（AaC），以研究其主要DNA损伤的突变谱，与由它们引起的疾病的突变特征相关。这个项目的核心假设是，由环境毒素产生的DNA损伤将导致不同的序列依赖性突变谱方式具体目的是：具体目的1：大体积DNA加合物的化学合成和鉴定含有寡核苷酸。特定目的2：细胞中大体积病变的突变谱。具体目标3：通过跨损伤合成聚合酶的损伤复制旁路。在这个项目结束时，我们将已经证明了环境毒素和突变谱之间的相互作用。这些研究将利用遗传，化学和光谱工具的组合来理解和操纵分子水平上的生物系统。