PARP-1 Signaling in DNA Damage and Cell Death

项目摘要 聚腺苷二磷酸核糖聚合酶-1（Poly（ADP-ribose），PAR）聚合酶-1（Poly（ADP-ribose），PARP-1）在DNA损伤反应中起重要作用。可以 被我们环境中丰富的DNA烷基化剂激活，或者被细胞分裂的副产物激活。 氧化应激或毒性。在轻微的DNA损伤中，PARP-1促进DNA修复过程。堵塞 PARP-1活性的降低使癌细胞对死亡敏感。这一概念得到了PARP抑制剂奥拉帕尼的很好支持 用于临床治疗癌症。相反，在严重的DNA损伤反应中， PARP-1导致大的DNA片段和半胱天冬酶非依赖性细胞死亡，称为parthanatos， 发生在许多器官系统中并广泛涉及不同的神经和非神经疾病， 包括中风和心肌梗塞后的缺血-再灌注损伤，谷氨酸兴奋毒性， 神经变性疾病、炎性损伤、活性氧诱导的损伤。这种类型的细胞 通过药理学抑制或PARP-1的遗传缺失可显著防止死亡。的重要性 PARP-1在细胞死亡中的作用在癌症领域也得到了重视，因为烷化剂已经用于治疗癌症。 化疗杀死癌细胞。因此，这些PARP-1研究提出了一个巨大的知识缺口， 在DNA损伤或氧化应激中调节信号传导，导致DNA修复/细胞存活或DNA损伤。 损伤/细胞死亡。PI以前的工作揭示了PAR的分子机制， 触发凋亡诱导因子（AIF）从线粒体释放并易位到细胞核， PARP-1依赖性细胞死亡（parthanatos）。最近，PI进一步通过识别 巨噬细胞移动抑制因子（MIF）作为一种新的核酸酶和死刑执行者， 将基因组DNA切割成大片段并导致神经元和癌细胞死亡。但不少 基本问题，包括1）MIF核酸酶活性如何响应DNA损伤进行调节， 神经元和癌细胞中的氧化应激; 2）DNA损伤中的PARP-1信号传导如何被调节， 在神经元和癌细胞的细胞死亡和细胞存活之间切换; 3）如何有效地干扰PARP- 1在DNA损伤中的信号传导，以防止过度的神经元损失，但增强癌细胞死亡，尚未被 回答这个MIRA项目的目标是获得对PARP-1的全面分子理解 DNA损伤中的信号传导，并发现PARP-1信号传导如何在轻度或中度损伤时被操纵。 严重的DNA损伤，从而防止神经元细胞死亡，但增强肿瘤细胞死亡。如果成功， 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， 治疗癌症或中风。此外，全面了解监管网络， PARP-1信号传导还可能导致开发用于治疗人类肿瘤的新的治疗策略。 由PARP-1激活引起的疾病。

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.