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.

隐性等位基因的突变已被牵涉到病因因素 在癌症和其他遗传疾病的发展中。 电离 辐射引起的突变通常会影响多个遗传基因座。 因此，辐射引起的损伤可能具有“发现”的高潜力 预先存在的突变或通过产生多焦点缺失，使该突变敏感 细胞对隐性未来突变的表型后果 等位基因已变成半齐的等位基因。 该建议探讨了 假设代理会导致突变表达的概率 在隐性等位基因中，其相对倾向是引起的 基因内（基因中的突变）和多焦点（突变导致 多个连续遗传基因座病变的缺失或修饰。 四个特工，伽玛辐射，2-氨基-N6-羟基甲胺（AHA），UVC 辐射和4-（9- acridinylamino）甲烷硫磺-m-烷氧化物（MAMSA），它 预计会引起不同比例的内核和多焦点 病变将是本研究的重点。 提出的实验是 致力于评估隐性处于隐性突变的模型 等位基因，通过量化和分析基因内与 纯合子，杂合和半合子基因靶标的多焦点病变。 将确定由选定药物造成的损害的光谱，并 反复接触这些诱变者对频率和 纯合基因的病变的特征将是 分析。 该提案中的模型假设多焦点病变 增加突变，癌症和其他遗传疾病的风险 第二个突变事件。 因此，这些调查的目的是 增强对可能控制互动的因素的理解 在基因内病变和多因素病变之间。