The Role of MDC1 in Genome Maintenance and Tumor Suppression

描述（由申请方提供）：基因组稳定性的维持对于生物体的健康至关重要。为了维持基因组的稳定性，细胞已经形成了一个称为DNA损伤反应途径的信号通路网络，以感知和修复DNA损伤。我们和其他人已经表明，MDC 1（DNA损伤检查点蛋白1的介导者，以前称为Kiaa 0170），一种以前未表征的蛋白质，调节DNA损伤反应途径的各个方面。我们还产生了MDC 1基因敲除小鼠，并表明MDC 1缺陷的细胞显示基因组不稳定性。这些观察结果支持了我们的中心假设，即MDC 1通过介导和促进遗传毒性应激后的信号转导途径来维持基因组稳定性。我们计划进一步探索MDC 1如何维持基因组稳定性的机制。此外，我们将使用MDC 1基因敲除小鼠作为动物模型来研究MDC 1在肿瘤抑制中的作用。具体目标是：1.探讨MDC 1的ATM依赖性磷酸化的生物学意义。我们绘制了一个ATM磷酸化位点MDC 1，我们的初步结果表明，这个磷酸化位点参与细胞周期检查点激活。我们将进一步探讨该磷酸化位点的调控和功能意义。2.研究MDC 1-拓扑异构酶II相互作用。我们的初步研究结果表明，MDC 1的BRCT结构域与拓扑异构酶II的磷酸化Ser 1524相互作用，这种相互作用调节脱连环检查点。我们将进一步研究MDC 1-拓扑异构酶II相互作用的调节，以及它如何调节去连锁检查点和基因组稳定性。3.研究基因组不稳定性在衰老和肿瘤发生中的作用。基因组不稳定性与过早衰老和肿瘤发生有关。我们将进一步评估MDC 1-/-小鼠中MDC 1的缺失是否会导致过早衰老和肿瘤发生。这些研究结果将为维持基因组稳定性和预防衰老及肿瘤发生提供新的分子机制。公共卫生相关性：DNA损伤反应途径缺陷与肿瘤发生有关。因此，了解DNA损伤反应途径有助于我们了解癌症的发生机制和预防方法，而且，鉴于许多癌症治疗都涉及DNA损伤诱导剂，因此，详细了解癌细胞中的DNA损伤反应途径及其缺陷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.