Regulation of the DNA damage response by the Mre11 complex

描述(由申请人提供)：这项续签申请利用先前在这项资助下开发的小鼠模型来测试依赖于Mre11复合体的DNA损伤反应减轻氧化和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中的肿瘤形成过程，作为DDR一般作用的范例。此外，我们将检验这样的假设，即氧化损伤带来的DNA损伤对DSB修复构成了显著的障碍，并且参与氧化损伤处理的酶，例如由电离辐射和仿射化合物引起的氧化损伤，提高了HR和NHEJ的效率。针对这一问题，已经建立了酵母菌和小鼠模型。最后，我们建立了新的突变小鼠，在其中可以评估Mre11复合体在对电离辐射和DNA复制压力的反应中不依赖于ATM的功能。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非常重要的意义，有可能阐明Mre11复合体对DDR网络的多个方面的功能影响。 公共卫生相关性：基因组不稳定是癌症的一个标志，DNA损伤反应中的缺陷是维持基因组稳定所必需的，与癌症以及与生殖、发育和神经缺陷相关的人类综合征有关。我们讨论了一个中央DNA损伤反应组件，Mre11复合体的功能。这种复合体与人类染色体不稳定综合征有关，与恶性肿瘤风险增加有关，也被发现在散发性癌症中存在缺陷。本申请中描述的实验检查了Mre11复合体，并有可能提供关于癌症易感性的潜在机制的见解，以及那些可能在治疗环境中提供合适的阻断靶点的机制。

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. PUBLIC HEALTH RELEVANCE: Genome instability is a hallmark of cancer, and defects in the DNA damage response, which is required for the maintenance of genome stability are associated with cancer as well as human syndromes associated with reproductive, developmental and neurological defects. We address the functions of a central DNA damage response component, the Mre11 complex. This complex has been implicated in human chromosome instability syndromes associated with increased risk of malignancy, and has also found to be defective in sporadic cancers. The experiments described in this application examine the Mre11 complex and have the potential to provide insights regarding the mechanisms underlying cancer predisposition, as well as those that may present suitable targets for interdiction in therapeutic settings.