PARP-1 Signaling in DNA Damage and Cell Death

DNA 损伤和细胞死亡中的 PARP-1 信号转导

基本信息

批准号：
9753761
负责人：
Yingfei Wang
金额：
$ 40.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-14 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753761
关键词：
Alkylating Agents Caspase Cell Death Cell Nucleus Cell Survival Cessation of life Cleaved cell Clinic DNA DNA Damage DNA Repair Development Environment Genetic Genomic DNA Glutamates Goals Inflammatory Injury Knowledge Lead Malignant Neoplasms Migration Inhibitory Factor Mitochondria Molecular Myocardial Infarction Neurodegenerative Disorders Neurologic Neurons Oxidative Stress Pharmacology Play Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Process Reactive Oxygen Species Reperfusion Injury Role Signal Transduction Stroke Toxic effect Work apoptosis inducing factor body system cancer cell cancer therapy cell type chemotherapy clinical application excitotoxicity human disease inhibitor/antagonist neoplastic cell neuron loss novel novel therapeutics nuclease post stroke prevent release factor response treatment strategy

项目摘要

Project summary Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) plays a pivotal role in DNA damage response. It can be activated either by the DNA alkylating agents abundant in our environment, or the byproducts of the cellular oxidative stress or toxicity. In response to mild DNA damage, PARP-1 facilitates DNA repair process. Blockage of PARP-1 activity sensitizes cancer cells to death. This concept is well supported by PARP inhibitor olaparib used in clinic for cancer therapy. In contrast, in response to severe DNA damage, excessive activation of PARP-1 causes the large DNA fragments and caspase-independent cell death designated parthanatos, which occurs in many organ systems and is widely involved in different neurologic and non-neurologic diseases, including ischemia-reperfusion injury after stroke and myocardial infarction, glutamate excitotoxicity, neurodegenerative diseases, inflammatory injury, reactive oxygen species–induced injury. This type of cell death is profoundly prevented by pharmacological inhibition or genetic deletion of PARP-1. The importance of PARP-1 in cell death has also been appreciated in the cancer field as alkylating agents have been used in chemotherapy to kill cancer cells. Therefore, these PARP-1 studies raise a huge knowledge gap how PARP-1 signaling is regulated in DNA damage or oxidative stress, leading to either DNA repair/cell survival or DNA damage/cell death. Previous works from the PI have revealed the molecular mechanisms by which PAR triggers apoptosis inducing factor (AIF) release from the mitochondria and translocation to the nucleus, leading to PARP-1 dependent cell death (parthanatos). Recently PI further made an important discovery by identifying macrophage migration inhibitory factor (MIF) as a novel nuclease and an executioner in parthanatos, which cleaves genomic DNA into large fragments and causes neuron and cancer cell death. However, many fundamental questions, including 1) how MIF nuclease activity is regulated in response to DNA damage and oxidative stress in neurons and cancer cells; 2) how PARP-1 signaling in DNA damage is regulated and switched between cell death and cell survival in neurons and cancer cells; 3) how to effectively interfere PARP- 1 signaling in DNA damage to prevent excess neuron loss but enhance cancer cell death, have not yet been answered. The goals of this MIRA project are to obtain a comprehensive molecular understanding of PARP-1 signaling in DNA damage and to discover how PARP-1 signaling can be manipulated in response to mild or severe DNA damage thereby preventing neuronal cell death but enhancing tumor cell death. If successful, the knowledge achieved from these studies will directly impact the clinical application of PARP inhibitors for treatment of cancer or stroke. Moreover, the comprehensive understanding of the regulatory networks of PARP-1 signaling may also lead to the development of novel therapeutic strategies for the treatment of human diseases caused by PARP-1 activation.

项目概要聚（ADP-核糖）（PAR）聚合酶-1（PARP-1）在 DNA 损伤反应中发挥着关键作用。被我们环境中丰富的 DNA 烷化剂或细胞的副产物激活为了应对轻微的 DNA 损伤，PARP-1 会促进 DNA 修复过程。 PARP-1 活性的降低使癌细胞对死亡敏感，这一概念得到了 PARP 抑制剂奥拉帕尼的充分支持。相反，在临床上用于癌症治疗，以应对严重的DNA损伤，过度激活。 PARP-1 会导致大 DNA 片段和不依赖于半胱天冬酶的细胞死亡，称为“parthanatos”，发生于许多器官系统，广泛涉及不同的神经系统和非神经系统疾病，包括中风和心肌梗塞后的缺血再灌注损伤、谷氨酸兴奋性毒性、神经退行性疾病、炎症损伤、活性氧诱导的损伤。 PARP-1 的药理学抑制或基因删除可有效预防死亡。 PARP-1 在细胞死亡中的作用在癌症领域也得到了重视，因为烷化剂已被用于因此，这些 PARP-1 研究提出了关于 PARP-1 的巨大知识差距。信号传导在 DNA 损伤或氧化应激中受到调节，导致 DNA 修复/细胞存活或 DNA PI 之前的工作已经揭示了 PAR 的分子机制。触发细胞凋亡诱导因子 (AIF) 从线粒体释放并易位至细胞核，导致最近PI通过鉴定进一步取得了重要发现。巨噬细胞迁移抑制因子（MIF）作为一种新型核酸酶和parthanatos中的刽子手，将基因组 DNA 切割成大片段并导致神经元和癌细胞死亡。基本问题，包括 1) 如何调节 MIF 核酸酶活性以响应 DNA 损伤，以及 2) DNA损伤中的PARP-1信号如何被调节以及神经元和癌细胞中细胞死亡和细胞存活之间的切换；3）如何有效地干扰 PARP- DNA 损伤中的 1 信号传导可防止神经元过度丢失，但会增强癌细胞死亡，但尚未得到证实这个 MIRA 项目的目标是获得对 PARP-1 的全面分子了解。 DNA 损伤中的信号传导，并发现如何操纵 PARP-1 信号传导以响应轻微或如果成功的话，严重的DNA损伤会阻止神经细胞死亡，但会增强肿瘤细胞的死亡。从这些研究中获得的知识将直接影响 PARP 抑制剂的临床应用此外，还需要全面了解癌症或中风的调节网络。 PARP-1 信号传导还可能导致人类新治疗策略的开发 PARP-1激活引起的疾病。