A SIGNALING PATHWAY SPECIFIC FOR ALKYLATION DAMAGE

摘要 DNA修复的关键第一步涉及识别基因组损伤，这反过来又激活了 征募效应器并解决病变的信号通路。然而，这个“传感器-- “传导者-中介者”范式一般适用于专用于修复 不同类型的DNA损伤仍不清楚。了解调解的信号事件 DNA烷基化损伤的识别和修复尤为重要，因为烷基化 化疗是癌症治疗中应用最广泛的全身疗法之一。我们的 初步研究表明，人类细胞有一种迄今未被识别的修复信号 高度特异地将烷基化修复因子募集到核焦点并将其联系在一起的途径 一种遗传性人类疾病的途径。由于似乎招募了多种烷基化修复因子 对于这些病灶，我们称之为核疤痕(专门的烷基化修复中心)。在这 建议，我们试图了解是否招募烷基化修复因子到这些部位 对解决烷基化修复至关重要(目标1)。我们将对上游的E3泛素连接酶进行鉴定， RNF113A，我们已经发现它在这一途径中发挥核心作用，并在孕激素中发生突变 毛发硫代营养不良综合征(目标2)。最后，我们将测试以这条路径为目标是否 在人类肿瘤模型中促进化疗增敏(目标3)。这些研究将大大增加我们的 了解细胞如何检测和激活DNA修复途径。因为烷基化修复是关键 为了逆转许多化疗药物的毒副作用，我们的工作将为 细胞如何对这种治疗做出反应，并可能揭示几个新的分子靶点 化学增敏。

Abstract A crucial first step in DNA repair involves the recognition of genome damage, which in turn activates signaling pathways that recruit effectors and resolve the lesion. However, whether this “sensor- transducer-mediator” paradigm is generally applicable to pathways dedicated to repairing each distinct type of DNA lesion remains unknown. Understanding the signaling events that mediate the recognition and repair of DNA alkylation damage is particularly important, since alkylation chemotherapy is one of the most widely used systemic modalities for cancer treatment. Our preliminary studies demonstrate that human cells have a heretofore unrecognized repair signaling pathway that is highly specific for recruiting alkylation repair factors to nuclear foci and link this pathway to an inherited human disease. Since multiple alkylation repair factors appear to be recruited to these foci, we have termed them nuclear SCARs (Specialized Centers for Alkylation Repair). In this proposal, we seek to understand whether recruitment of alkylation repair factors to these sites is critical for resolution of alkylation repair (Aim 1). We will characterize the upstream E3 ubiquitin ligase, RNF113A, which we have found to play a central role in this pathway and is mutated in the progeroid syndrome trichothiodystrphy (Aim 2). Finally, we will test whether targeting this pathway could promote chemosensitization in human tumor models (Aim 3). These studies will greatly increase our understanding of how cells detect and activate DNA repair pathways. Since alkylation repair is critical for reversing the toxic effects of many chemotherapy agents, our work will provide new insights into how cell respond to such therapy, and may reveal several novel molecular targets for chemosensitization.