IONIZING RADIATION INDUCED MUTATION IN ENDOGENOUS GENES

电离辐射诱发内源基因突变

• 批准号: 3253844
• 负责人: W DAVID SEDWICK
• 金额: $ 21.9万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-03-01 至 1994-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3253844
• 关键词: DNA damage; X ray; aminoacridines; bleomycin; carmustine; gene deletion mutation; gene mutation; ionizing radiation; mutagens; point mutation; polymerase chain reaction; radiation carcinogenesis; radiation genetics; radiobiology; southern blotting; tissue /cell culture

Mutations at recessive alleles have been implicated as a causative factor in the development of cancer and other genetic diseases. Ionizing radiation causes mutations which often affect multiple genetic loci. Radiation-induced damage, therefore, may have a high potential to "uncover" pre-existing mutations or by producing multilocus deletions, sensitize the cells to the phenotypic consequences of future mutations in recessive alleles which have become hemizygous. This proposal explores the hypothesis that the probability an agent will cause expression of mutations at recessive alleles is dependent on its relative propensity to cause intragenic (mutations within a gene) and multilocus (mutations resulting in deletion or modification of multiple contiguous genetic loci) lesions. Four agents, gamma radiation, 2-amino-N6-hydroxyadenine (AHA), UVC radiation, and 4-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA), which are expected to cause different proportions of intragenic and multilocus lesions, will be the focus of this study. Proposed experiments are directed toward evaluation of a model for expressed mutations at recessive alleles, through quantification and analysis of intragenic versus multilocus lesions at homozygous, heterozygous and hemizygous gene targets. The spectrum of damage caused by the selected agents will be determined and the effects of repeated exposure to these mutagens on the frequency and characteristics of lesions which inactivate a homozygous gene will be analyzed. The model in this proposal postulates that multilocus lesions enhance the risk for mutation, cancer and other genetic diseases from a second mutational event. Accordingly, the goal of these investigations is to augment the understanding of factors which may govern the interaction between intragenic lesions and multilocus lesions.

隐性等位基因突变被认为是一个致病因素 癌症和其他遗传疾病的发展。 电离 辐射引起的突变通常会影响多个基因位点。 因此，辐射引起的损伤可能很有可能“被发现” 预先存在的突变或通过产生多位点缺失，使 细胞对未来隐性突变的表型后果 已成为半合子的等位基因。 该提案探讨了 假设某种物质引起突变表达的概率 隐性等位基因取决于其引起的相对倾向 基因内（基因内的突变）和多位点（导致 多个连续基因位点的缺失或修饰）病变。 四剂、伽马射线、2-氨基-N6-羟基腺嘌呤 (AHA)、UVC 辐射和 4-(9-吖啶氨基)甲磺酰苯胺 (mAMSA)， 预计会导致不同比例的基因内和多位点 病变，将是本研究的重点。 提议的实验是 旨在评估隐性表达突变的模型 等位基因，通过基因内与基因内的定量和分析 纯合子、杂合子和半合子基因靶点的多位点损伤。 所选药剂造成的损害范围将被确定并 反复接触这些诱变剂对频率和频率的影响 使纯合基因失活的病变特征将是 分析了。 该提案中的模型假设多位点病变 增加基因突变、癌症和其他遗传疾病的风险 第二次突变事件。 因此，这些调查的目标是 增强对可能控制相互作用的因素的理解 介于基因内病变和多位点病变之间。