Repair Proteins: Interface between Cell Death & Survival

描述（由申请人提供）：错配修复（MMR）蛋白的肿瘤抑制功能- MMR蛋白具有作为肿瘤抑制因子的双重作用。它们的修复功能确保基因组稳定性; MMR依赖的DNA损伤反应通过诱导细胞死亡消除受损细胞。任何一种功能的缺陷都会导致基因组不稳定性的增加和细胞死亡的逃避，这是癌症的两个标志。因此，MMR缺陷显著地促成癌发生、化疗失败和继发性肿瘤生长。对于肿瘤治疗的进步，了解MMR蛋白的肿瘤抑制功能是必需的。DNA损伤反应中的MMR蛋白。在过去的几十年中，MMR通路已经被广泛研究。相比之下，虽然存在一个MMR依赖的损伤响应被广泛接受，其机制方面在很大程度上是未知的。在MMR依赖性损伤反应中诱导的信号级联需要研究。MMR蛋白在细胞死亡和存活之间的界面。作为DNA损伤传感器，MutS同源蛋白是鉴定损伤的性质和程度、其加工和诱导适当反应的优秀候选者。导致细胞死亡或存活的途径的诱导需要严格的调节和协调。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目前尚不清楚。MMR相关损伤响应的系统研究。- 对DNA损伤反应（Aim 1）中总体细胞存活率和特定凋亡信号传导改变的遗传学研究将与突变蛋白（Aim 2）相关的功能缺陷的生物化学研究相补充，并与修复要求进行比较。将根据MMR蛋白功能和DNA损伤信号（Aim 3）分析参与MMR依赖性细胞死亡信号级联的下游蛋白。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定点上的肿瘤抑制作用，并确定MMR依赖性损伤反应的分子机制。对这一机制的理解将有助于实现该项目的长期目标，该项目旨在改善针对个人需求的癌症患者的诊断和治疗。

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.