Repair Proteins: Interface between Cell Death & Survival

描述(申请人提供)：错配修复(MMR)蛋白的肿瘤抑制功能-MMR蛋白具有肿瘤抑制蛋白的双重作用。它们的修复功能确保了基因组的稳定性；依赖MMR的DNA损伤反应通过诱导细胞死亡来消除受损细胞。任何一种功能的缺陷都会导致基因组的不稳定性增加和逃避细胞死亡，这是癌症的两个特征。因此，MMR缺陷与肿瘤的发生、化疗失败和继发性肿瘤生长密切相关。为了在肿瘤治疗方面取得进展，必须了解MMR蛋白的肿瘤抑制功能。DNA损伤反应中的MMR蛋白。在过去的几十年里，MMR途径得到了广泛的研究。相反，尽管依赖于MMR的损伤响应的存在被广泛接受，但其机理方面在很大程度上是未知的。在MMR依赖的损伤反应中诱导的信号级联反应需要研究。位于细胞死亡和存活交界处的MMR蛋白。作为DNA损伤传感器，MutS同源蛋白是识别损伤的性质和程度、处理和诱导适当反应的极佳候选者。导致细胞死亡或存活的通路的诱导需要严格的调控和协调。目前尚不清楚初始信号的性质以及MMR蛋白在不同途径的协调中发挥作用的机制和程度。MMR依赖的损伤响应的系统研究。-关于总细胞存活率变化和DNA损伤反应中的特定凋亡信号(Aim1)的遗传学研究将补充与突变蛋白相关的功能缺陷(AIM2)的生化研究，并与修复要求进行比较。参与MMR依赖的细胞死亡信号级联的下游蛋白将根据MMR蛋白功能和DNA损伤信号(Aim3)进行分析。预期结果：这项研究将首次深入了解MMR蛋白在细胞死亡和存活之间的决策点的肿瘤抑制作用，并确定MMR依赖的损伤反应的分子机制。对这一机制的理解将有助于该项目的长期目标，该项目旨在改善癌症患者的诊断和治疗，以满足个人的需求。

DESCRIPTION (provided by applicant): Tumor suppressor function of mismatch repair (MMR) proteins - MMR proteins have a dual role as tumor suppressors. Their repair function ensures genome stability; MMR-dependent DNA damage response eliminates damaged cells by inducing cell death. Defects in either function result in increased genome instability and evasion of cell death, two hallmarks of cancer. Hence, MMR defects contribute significantly to carcinogenesis, failure of chemotherapy and secondary tumor growth. For an advancement in tumor therapy, an understanding of the tumor suppressor function of MMR proteins is mandatory. MMR proteins in DNA damage response. The MMR pathway has been investigated extensively over the past decades. In contrast, though the existence of a MMR-dependent damage response is widely accepted, its mechanistic aspects are largely unknown. The signaling cascade induced in MMR-dependent damage response needs to be investigated. MMR proteins at the interface between cell death and survival. As DNA damage sensors, MutS homologous proteins are excellent candidates for the identification of the nature and extent of damage, its processing and the induction of appropriate responses. The induction of pathways resulting in either cell death or survival requires tight regulation and coordination. The nature of the initial signal, and the mechanism and extent to which MMR proteins function in the coordination of different pathways is currently unknown. A systematic investigation of MMR-dependent damage response. - Genetic studies on alterations in overall cell survival and specific apoptotic signaling in DNA damage response (Aim1) will be complemented with biochemical studies of functional defects associated with mutant proteins (Aim2) and compared to requirements in repair. Downstream proteins involved in the MMR-dependent cell death signaling cascade will be analyzed in dependence of MMR protein function and the DNA damage signal (Aim3). Expected Outcome: This research will provide first insights into the tumor suppressor role of MMR proteins at the decision point between cell death and survival, and identify the molecular mechanism of MMR-dependent damage response. An understanding of this mechanism will funnel into the long term goal of this project that is aimed at the improvement of diagnosis and treatment of cancer patients tailored towards the individual's needs.