权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

DNA Adduct-Induced Mutagenesis

DNA加合物诱导突变

基本信息

批准号：
7647846
负责人：
Michael P Stone
金额：
$ 25.17万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-02-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7647846
关键词：
Aflatoxin B Aflatoxin B1 Aflatoxins Aldehydes Alkylation Anabolism Apoptosis Base Pairing Binding Biochemical Biological Biological Process Bypass Cancer Etiology Cereals Characteristics Chemicals Chemistry Chronic Chronic Hepatitis B Collaborations Complex Connecticut Crystallography Cytochrome P450 DNA DNA Adducts DNA Damage DNA Polymerase beta DNA biosynthesis DNA-Directed DNA Polymerase Data Defect Deoxyguanosine Enzymes Epidemiology Epoxy Compounds Equilibrium Erythro Etiology Exhibits Exposure to Family Food Generations Genes Genome Stability Goals Hepatitis B Hepatitis B Virus Human Inflammation Ionizing radiation Lead Lesion Lipid Peroxidation Maintenance Malignant Neoplasms Malignant neoplasm of liver Malondialdehyde Metabolism Molecular Conformation Mutagenesis Mutagens Mutation Mycotoxins Nucleotides Pathway interactions Peanuts - dietary Polymerase Process Prostaglandins Protein p53 Reporting Research Rice Secondary Lesion Signal Transduction Site Somatic Cell Somatic Mutation Source Structure Structure-Activity Relationship Thymine Tumor Suppressor Genes Universities adduct aflatoxin B1-formamidopyrimidine anomer base epimerization oxidation oxidative damage repaired response structural biology thymine glycol

项目摘要

This proposal focuses upon the chemical and structural biology of three types of DNA damage. Malondialdehyde (MDA), produced by lipid peroxidation and prostaglandin biosynthesis, reacts with DNA to form an adduct known as OPdG, which is implicated in human cancer. Aflatoxin B (AFB1), a highly mutagenic mycotoxin, is a contaminant of food. Epidemiological evidence suggests that it acts synergistically with the hepatitis B virus to promote hepatic cancer; these cancers often exhibit mutations in the p53 tumor suppressor gene. The cytochrome P450 oxidation product of AFB1 alkylates the N7 atom of deoxyguanosine. Oxidative damage to thymine from ionizing radiation produces 5,6-dihydroxy-dihydro-2'-thymine (thymine glycol; Tg). Tg inhibits replication by prokaryotic and eukaryotic DNA polymerases, and is implicated in the etiology of human cancer, perhaps associated with the generation of double strand breaks in DNA. The emphasis on these three types of DNA damage is predicated upon the observation that when present in DNA, each of these types of damage can undergo further chemistry depending upon whether the DNA exists in duplex or in single-stranded form, and also depending upon the sequence and identity of the complementary nucleotide in duplex DNA. Thus, in each case the biological response to the lesion is anticipated to depend upon its downstream chemistry in DNA. Some of the secondary lesions; e.g., the AFB1-N7-dG FAPy lesions, are more deleterious than are the initial lesions. This research seeks to delineate the complex chemistry of these lesions in DNA, and to define underlying structure-activity relationships, in an effort to understand their interactions with DNA processing enzymes, such as damage bypass polymerases. To accomplish this, a combination of biochemical and biophysical approaches will be utilized. NMR will be used to determine the structures of site-specific DNA damage in oligodeoxynucleotides. Crystallography will be used to determine structures of sitespecifically damaged oligodeoxynucleotides in complex with DNA polymerases. The resulting structural data will be interpreted in collaboration with colleagues at Vanderbilt University and the University of Connecticut. The ultimate goal is to understand complex cellular responses to specific types of DNA damage.

这一建议集中在化学和结构生物学的三种类型