Regulation of the DNA damage response by the Mre11 complex

描述（由申请人提供）：这项更新申请利用先前在该资助下开发的小鼠模型来测试Mre11复合体依赖的DNA损伤反应减轻氧化和致癌基因诱导的基因毒性应激的致癌潜力的假设。我们专注于乳腺上皮的致瘤过程，作为DDR一般作用的一个范例。此外，我们将验证氧化损伤引起的DNA损伤对DSB修复构成重大障碍的假设，以及参与氧化损伤处理的酶，如电离辐射和拟辐射化合物引起的氧化损伤，可提高HR和NHEJ的效率。为此，我们建立了酵母和小鼠模型。最后，我们建立了新的突变小鼠，在这些小鼠中，可以评估Mre11复合物在电离辐射和DNA复制应激反应中的ATM独立功能。鉴于DDR在肿瘤抑制、减数分裂和免疫系统发育中的重要性，本文提出的研究方案具有重要意义，有可能阐明Mre11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.