Role of poly(ADP-ribose) polymerase-1 as a controlling switch between DNA damage-induced apoptosis and necrosis

聚（ADP-核糖）聚合酶-1 作为 DNA 损伤诱导的细胞凋亡和坏死之间控制开关的作用

• 批准号: 155257-2006
• 负责人: Shah, Girish
• 金额: $ 2.79万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2007
• 资助国家: 加拿大
• 起止时间: 2007-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=364179
• 关键词: Role; poly; ADP; ribose; polymerase

ROLE OF POLY(ADP-RIBOSE) POLYMERASE-1 AS A CONTROLLING SWITCH BETWEEN DNA DAMAGE-INDUCED APOPTOSIS AND NECROSIS         In a rapid response to DNA damage, poly(ADP-ribose) polymerase-1 (PARP), a nuclear enzyme present in higher eukaryotes, is catalytically activated to consume NAD and form polymers of ADP-ribose, which transiently modify functions of selected chromatin structure- and DNA metabolism-related proteins. Recent studies, including those from our NSERC-supported research, have shown in different models of cell death that early PARP activation in response to high levels of DNA damage can influence key initiating events which can lead to either apoptosis or necrosis, such as depletion of NAD and ATP, nuclear translocation of apoptosis inducing factor, intracellular acidification, etc. Hence, we hypothesize that in a given cell exposed to varying levels of DNA damage, the decision to die by apoptosis or necrosis is influenced by a balance of these immediate actions of PARP. We will use cells with or without functional PARP, cells expressing wild type or caspase 3-resistant mutant PARP; and cells which are proficient or deficient in proton-removal pump Na/H+ exchanger-1 with or without functional PARP. In these models, we will examine mode of death in responses to different levels of DNA damage and correlate it with PARP-related events that control the mode of cell death.         The specific objectives of the project are to determine: 1) Whether the presence and actions of PARP influence apoptotic or necrotic response of cells to varying levels of DNA damage; 2) The mechanism by which cleavage of PARP by caspases 3 promotes apoptosis; 3) The mechanism by which PARP-mediated cellular acidification blocks apoptosis and allows necrosis; and 4) The death-related genes whose expression is controlled by PARP during initiation of apoptosis or necrosis.

聚ADP-核糖聚合酶-1在DNA损伤诱导的细胞凋亡和坏死中的调控作用 在对DNA损伤的快速反应中，聚（ADP-核糖）聚合酶-1（PARP），一种存在于高等真核生物中的核酶，被催化激活以消耗NAD并形成ADP-核糖的聚合物，其瞬时修饰选定的染色质结构和DNA代谢相关蛋白的功能。最近的研究，包括来自我们NSERC支持的研究的研究，已经在不同的细胞死亡模型中表明，响应于高水平DNA损伤的早期PARP激活可以影响关键的起始事件，其可以导致凋亡或坏死，例如NAD和ATP的消耗，凋亡诱导因子的核转位，细胞内酸化等。我们假设在暴露于不同水平DNA损伤的给定细胞中，通过凋亡或坏死死亡的决定受到PARP这些直接作用的平衡的影响。我们将使用具有或不具有功能性PARP的细胞、表达野生型或半胱天冬酶3抗性突变体PARP的细胞;以及具有或不具有功能性PARP的质子去除泵Na/H+交换器-1熟练或缺乏的细胞。在这些模型中，我们将检查响应于不同水平的DNA损伤的死亡模式，并将其与控制细胞死亡模式的PARP相关事件相关联。 该项目的具体目标是确定：1）PARP的存在和作用是否影响细胞对不同水平DNA损伤的凋亡或坏死反应; 2）半胱天冬酶3切割PARP促进凋亡的机制; 3）PARP介导的细胞酸化阻断凋亡并允许坏死的机制;（4）在细胞凋亡或坏死启动过程中受PARP调控表达的死亡相关基因。