The Role of MDC1 in Genome Maintenance and Tumor Suppression

描述(由申请人提供)：保持基因组的稳定性对生物体的福祉至关重要。为了保持基因组的稳定性，细胞已经开发了一个称为DNA损伤反应通路的信号通路网络来感知和修复DNA损伤。我们和其他人已经证明，MDC1(DNA损伤检查点蛋白1的介体，以前被称为Kiaa0170)是一个以前未被描述的蛋白质，它调节DNA损伤反应途径的各个方面。我们还产生了MDC1基因敲除小鼠，并表明MDC1基因缺陷的细胞表现出基因组的不稳定性。这些观察结果支持我们的中心假设，即MDC1通过调节和促进遗传毒性应激后的信号转导途径来维持基因组的稳定性。我们计划进一步探索mdc1维持基因组稳定性的机制。此外，我们还将使用mdc1基因敲除小鼠作为动物模型，研究mdc1基因在肿瘤抑制中的作用。其具体目的是：1.探讨ATM依赖的MDC1磷酸化的生物学意义。我们已经在MDC1上定位了一个ATM磷酸化位点，初步结果表明该磷酸化位点参与了细胞周期检查点的激活。我们将进一步探讨该磷酸化位点的调控及其功能意义。2.研究MDC1与拓扑异构酶II的相互作用。我们的初步结果表明，MDC1的BRCT结构域与拓扑异构酶II的磷酸化Ser1524相互作用，这种相互作用调节十分之一检查点。我们将进一步研究MDC1-拓扑异构酶II相互作用的调节，以及它如何调节十分之一检查点和基因组稳定性。3.探讨基因组不稳定性在衰老和肿瘤发生中的作用。基因组不稳定与过早衰老和肿瘤发生有关。我们将进一步评估mdc1基因缺失是否会导致mdc1-/-小鼠过早衰老和肿瘤形成。这些研究的结果将为维持基因组稳定、防止衰老和肿瘤发生提供新的分子机制。公共卫生相关性：DNA损伤反应通路缺陷与肿瘤发生有关。因此，了解DNA损伤反应通路将有助于我们了解癌症是如何发生的，以及如何预防癌症。此外，鉴于许多癌症治疗都涉及DNA损伤诱导剂，对癌细胞中DNA损伤反应途径及其缺陷的详细了解将有助于我们针对特定癌症设计靶向治疗。

DESCRIPTION (provided by applicant): Maintenance of genomic stability is critical for the well-being of organisms. To maintain genomic stability, cells have developed a network of signaling pathways called the DNA damage response pathway to sense and repair DNA damage. We and others have shown that MDC1 (Mediator of DNA Damage Checkpoint Protein 1, previously known as Kiaa0170), a previously uncharacterized protein, regulates various aspects of the DNA damage response pathway. We have also generated MDC1 knockout mice and shown that cells deficient in MDC1 display genomic instability. These observations support our central hypothesis that MDC1 maintains genomic stability by mediating and facilitating signal transduction pathways following genotoxic stress. We plan to further explore the mechanism of how MDC1 maintains genomic stability. In addition, we will examine the role of MDC1 in tumor suppression using the MDC1 knockout mouse as an animal model. The specific aims are: 1. Explore the biological significance of ATM-dependent phosphorylation of MDC1. We have mapped an ATM phosphorylation site on MDC1, and our preliminary results suggest that this phosphorylation site is involved in the cell cycle checkpoint activation. We will further explore the regulation and functional significance of this phosphorylation site. 2. Investigate the MDC1-topoisomerase II interaction. Our preliminary results suggest that the BRCT domain of MDC1 interacts with phospho-Ser1524 of topoisomerase II, and this interaction regulates the decatenation checkpoint. We will further investigate the regulation of the MDC1-topoisomerase II interaction, and how it regulates the decatenation checkpoint and genomic stability. 3. Investigate the role of genomic instability in aging and tumorigenesis. Genomic instability has been linked to both premature aging and tumorigenesis. We will further evaluate whether loss of MDC1 results in premature aging and tumorigenesis in MDC1-/- mice. Results from these studies will provide new molecular mechanisms of the maintenance of genomic stability and the prevention of aging and tumorigenesis. PUBLIC HEALTH RELEVANCE: Defective DNA damage response pathway is linked to tumorigenesis. Therefore, understanding the DNA damage response pathway will help us understand how cancer arises and how to prevent it. In addition, given that many cancer therapies involve DNA damage-inducing agent, a detailed understanding of the DNA damage response pathway and its defects in cancer cells will help us to design targeted therapy for specific cancers.