Regulation of the DNA damage response by the Mre11 complex

Mre11 复合物对 DNA 损伤反应的调节

基本信息

批准号：
8415942
负责人：
John HJ Petrini
金额：
$ 55.24万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415942
关键词：
ATM activation Address Affect Alleles Apoptosis Biochemical Biological Cells Chromosomal Instability Complex DNA DNA Damage DNA Double Strand Break DNA Repair DNA biosynthesis DNA damage checkpoint DNA lesion Defect Development Disease ERBB2 gene Embryo Enzymes Excision Exhibits Functional disorder Funding Genome Stability Genomic Instability Genotoxic Stress Goals Grant Hematopoietic stem cells Human Human Chromosomes Immune system Inherited Ionizing radiation Laboratories Lead Lesion Maintenance Malignant Neoplasms Mammalian Cell Mammary Neoplasms Mammary Tumorigenesis Mediating Meiosis Modeling Molecular Mouse Strains Mus Mutant Strains Mice Mutation NBS1 gene Neurologic Nonhomologous DNA End Joining Oncogenes Oncogenic Oxidative Stress Oxygen Pathway interactions Predisposition Process Production Reactive Oxygen Species Regulation Relative (related person)Relative Risks Reporter Research Risk Role S Phase Saccharomyces cerevisiae Stress Syndrome System Testing Therapeutic Tumor Biology Tumor Suppression Work Yeast Model System Yeasts in vivo indexing insight mammary epithelium mouse model mutant novel overexpression oxidative DNA damage oxidative damage programs repair enzyme repaired reproductive research study response systems research telomere tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): This renewal application exploits mouse models previously developed under the auspices of this grant to test the hypothesis that Mre11 complex-dependent DNA damage responses mitigate the oncogenic potential of oxidative and oncogene induced genotoxic stress. We focus on tumorigenic processes in mammary epithelium with as an exemplar of the general role of the DDR. In addition, we will test the hypothesis that DNA lesions imparted by oxidative damage pose a significant barrier to DSB repair, and that the enzymes involved in the processing of oxidative lesions such as those caused by ionizing radiation and radiomimetic compounds enhance the efficiency of both HR and NHEJ. For this issue, yeast and mouse models have been established. Finally, we have established novel mutant mice in which the ATM- independent functions of the Mre11 complex in the response to ionizing radiation and DNA replication stress can be assessed. Given the importance of the DDR in tumor suppression, meiosis, and development of the immune system, the research program proposed herein is highly significant with the potential to illuminate the functional impact of the Mre11 complex on multiple aspects of the DDR network.

描述（由申请人提供）：此更新应用利用了先前在该赠款的主持下开发的小鼠模型，以检验以下假设：MRE11复合依赖性DNA损伤反应可减轻氧化和癌基因诱导的基因毒性应力的致癌潜力。我们专注于乳腺上皮的致瘤过程，并作为DDR的一般作用的典范。此外，我们将检验以下假设：氧化损伤所赋予的DNA病变构成了DSB修复的显着障碍，并且参与加工氧化病变的酶（例如电离辐射和放射性映射化合物引起的）促进了HR和NHEJ的效率。对于此问题，已经建立了酵母和鼠标模型。最后，我们建立了新型突变小鼠，其中MRE11复合物在对电离辐射的响应和DNA复制应力中的ATM独立功能可以评估。鉴于DDR在肿瘤抑制，减数分裂和免疫系统的发展中的重要性，本文提出的研究计划非常重要，有可能阐明MRE11复合物对DDR网络多个方面的功能影响。