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，因此我们预防癌症的努力的成功在于我们能够理解细胞如何在面对DNA复制错误和细胞内和细胞外试剂对DNA化学稳定性的挑战时保持基因组的保真度。细胞已经进化出称为检查点的复杂调控网络，以感知DNA损伤并协调DNA修复，DNA复制和细胞周期进程。新的蛋白质MDC 1（DNA损伤检查点蛋白1的介体）最近出现作为一个关键的球员在细胞响应DNA损伤，因为它是必要的ATM激酶传递DNA损伤信号的检查点机制。本研究的目的是提供结构洞察细胞周期检查点控制的分子机制。我们假设MDC 1的模块化结构允许其作为分子枢纽通过多种动态和稳定的蛋白质-蛋白质相互作用来介导DNA损伤反应。我们提出了一个多层次的方法来确定MDC 1的结构生物化学相结合的生物化学与低和高分辨率的生物物理技术。

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.