ADP-RIBOSYL TRANSFERASE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.