Structural Biology of MDC1, a Novel Checkpoint Mediator

描述(由申请人提供)： 由于基因组完整性的丧失是癌症的标志之一，我们预防癌症的努力的成功在于我们有能力了解细胞如何在面对DNA复制错误和细胞内外因素对DNA化学稳定性的挑战时保持基因组的保真度。细胞进化出复杂的调控网络，称为检查点，以感知DNA损伤并协调DNA修复、DNA复制和细胞周期进展。最近，新的蛋白MDC1(DNA损伤检查点蛋白1的介体)在细胞对DNA损伤的反应中发挥了关键作用，因为ATM激酶是将DNA损伤信号传递到检查点机制所必需的。这项研究的目的是为细胞周期检查点控制的分子机制提供结构性的见解。我们假设MDC1的模块化结构使其能够作为分子枢纽，通过多个动态和稳定的蛋白质-蛋白质相互作用来调节DNA损伤反应。我们提出了一个多层次的方法，通过结合生物化学和低分辨率和高分辨率生物物理技术来确定MDC1的结构生物化学。

DESCRIPTION (provided by applicant): Since the loss of genomic integrity is one of the hallmarks of cancer, the success of our efforts to prevent cancer lies in our ability to understand how cells maintain the fidelity of the genome in the face of DNA replication errors and challenges to the chemical stability of DNA by both intracellular and extracellular agents. Cells have evolved complex regulatory networks called checkpoints to sense DNA damage and coordinate DNA repair, DNA replication, and cell-cycle progression. The novel protein MDC1 (Mediator of DNA Damage Checkpoint protein 1) recently emerged as a critical player during the cellular response to DNA damage because it is necessary for the ATM kinase to transmit DNA damage signals to the checkpoint machinery. The goal of this research is to provide structural insight into the molecular mechanisms of cellcycle checkpoint control. We hypothesize that the modular architecture of MDC1 allows it to act as a molecular hub to mediate the DNA damage response through multiple dynamic and stable protein-protein interactions. We propose a multi-tiered approach to determine the structural biochemistry of MDC1 by combining biochemistry with both low- and high-resolution biophysical techniques.