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 募集效应子并解决损伤的信号通路。然而，无论是这个“传感器- “转导-介导”范式通常适用于专门修复每个细胞的通路。 一种独特的DNA损伤类型仍然未知。了解介导细胞凋亡的信号事件 DNA烷基化损伤的识别和修复特别重要，因为烷基化 化学疗法是癌症治疗中最广泛使用的系统方式之一。我们 初步研究表明，人类细胞具有迄今为止未被认识到的修复信号， 这是一条高度特异性的途径，用于将烷基化修复因子募集到核灶，并将其与 人类遗传疾病的途径。由于多个烷基化修复因子似乎被招募 对于这些病灶，我们称它们为核SCAR（烷基化修复专门中心）。在这 建议，我们试图了解是否招募烷基化修复因子，这些网站是 对于烷基化修复的解决至关重要（目标1）。我们将表征上游E3泛素连接酶， RNF 113 A，我们发现它在这一通路中起着核心作用，并在早衰症中发生突变。 综合征型甲状腺功能障碍（Aim 2）。最后，我们将测试是否针对这一途径， 促进人类肿瘤模型中的化学增敏作用（目的3）。这些研究将大大提高我们的 了解细胞如何检测和激活DNA修复途径。由于烷基化修复至关重要 逆转许多化疗药物的毒性作用，我们的工作将提供新的见解， 细胞如何对这种疗法作出反应，并可能揭示一些新的分子靶点， 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.