Regulation of the DNA damage response by the Mre11 complex

描述（由申请人提供）：本更新申请利用先前在本授权的支持下开发的小鼠模型来检验Mre 11复合物依赖性DNA损伤反应减轻氧化和致癌基因诱导的遗传毒性应激的致癌潜力的假设。我们专注于乳腺上皮的肿瘤发生过程，作为DDR的一般作用的一个例子。此外，我们将测试的假设，即DNA损伤所赋予的氧化损伤构成了一个显着的障碍，DSB修复，并参与氧化损伤的处理，如电离辐射和拟放射性化合物引起的酶提高效率的HR和NHEJ。针对这一问题，已经建立了酵母和小鼠模型。最后，我们已经建立了新的突变小鼠，其中可以评估Mre 11复合物在电离辐射和DNA复制应激反应中的ATM非依赖性功能。鉴于DDR在肿瘤抑制、减数分裂和免疫系统发育中的重要性，本文提出的研究计划具有高度意义，有可能阐明Mre 11复合物对DDR网络多个方面的功能影响。

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.