ADP-RIBOSYL TRANSFERASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 腺苷二磷酸核糖转移酶(ADPRT)，又称PARP-1，是一种染色质相关酶，在DNA修复、转录调控和控制细胞死亡中发挥作用。ADPRT启动DNA损伤检测和修复途径，纠正DNA结构中的断裂，从而维持我们基因组的完整性和稳定性。ADPRT的抑制剂使细胞对癌症治疗中使用的DNA损伤剂敏感，因此ADPRT已成为癌症治疗的一个有前途的靶点。ADPRT的催化活性受到DNA链断裂的显著刺激。我们的目标是从结构上确定ADPRT激活的分子机制。了解激活机制可能会揭示控制ADPRT活性的新策略。我们目前正在研究ADPRT与DNA的复合体中的DNA结合片段。DNA结合的模式目前尚不清楚。我们的数据将被用于设计基于结构的突变体，以测试ADPRT结构域的功能。我们的长期目标是了解ADPRT如何识别DNA结构中的断裂，DNA结合如何触发ADPRT催化活性，以及ADPRT激活如何启动DNA损伤修复。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ADP-ribosyl transferase (ADPRT), also known as PARP-1, is a chromatin-associated enzyme that functions in DNA repair, transcriptional regulation, and controlled cell death. ADPRT initiates a DNA damage detection and repair pathway that corrects breaks in the structure of DNA, thereby functioning to maintain the integrity and stability of our genomes. Inhibitors of ADPRT sensitize cells to DNA-damaging agents used in cancer therapy; therefore ADPRT has emerged as a promising target for cancer treatment. The catalytic activity of ADPRT is dramatically stimulated by DNA strand breaks. Our objective is to structurally define the molecular mechanism of ADPRT activation. Understanding the mechanism of activation might reveal novel strategies for controlling ADPRT activity. We are currently focusing on a DNA-binding fragment of ADPRT in complex with DNA. The mode of DNA binding is currently unknown. Our data will be used to design structure-based mutants that test the function of this domain of ADPRT. Our long-term goals are to understand how ADPRT recognizes breaks in DNA structure, how DNA binding triggers ADPRT catalytic activity, and how ADPRT activation initiates DNA damage repair.