PARP-1 Signaling in DNA Damage and Cell Death

项目总结 聚腺苷二磷酸核糖(PAR)聚合酶-1(PARP-1)在DNA损伤反应中起着关键作用。它可以是 被我们环境中丰富的DNA烷化剂激活，或者是细胞的副产品 氧化应激或毒性。对于轻微的DNA损伤，PARP-1促进了DNA修复过程。堵塞 PARP-1活性的降低使癌细胞对死亡敏感。PARP抑制剂olaparib很好地支持了这一概念 临床上用于癌症治疗。相反，为了应对严重的DNA损伤，过度激活 PARP-1导致大的DNA片段和caspase非依赖性的细胞死亡，称为甲胎蛋白，这是 发生在许多器官系统中，并广泛参与不同的神经和非神经疾病， 包括中风和心肌梗死后的缺血再灌注损伤，谷氨酸兴奋毒性， 神经退行性疾病、炎症性损伤、活性氧诱导的损伤。这种类型的细胞 通过对PARP-1的药理抑制或基因缺失，可以有效地防止死亡。重要的是 PARP-1在细胞死亡中的作用在癌症领域也得到了重视，因为烷化剂已用于 用化疗杀死癌细胞。因此，这些PARP-1研究提出了一个巨大的知识缺口，即PARP-1是如何 信号在DNA损伤或氧化应激中受到调节，导致DNA修复/细胞存活或DNA 损伤/细胞死亡。之前来自PI的工作揭示了PAR的分子机制 触发凋亡诱导因子(AIF)从线粒体释放并移位到细胞核，导致 PARP-1依赖的细胞死亡(帕拉那托斯)。最近，Pi又有了一个重要发现，他识别出 巨噬细胞移动抑制因子(MIF)作为一种新的核酸酶和甲状旁腺的刽子手， 将基因组DNA裂解成大片段，导致神经元和癌细胞死亡。然而，许多人 基本问题，包括1)如何调节MIF核酸酶活性以响应DNA损伤和 神经元和癌细胞中的氧化应激；2)DNA损伤中PARP-1信号是如何调节和 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信号在DNA损伤中防止过度神经元丢失但促进癌细胞死亡，目前还没有 回答。该MIRA项目的目标是获得对PARP-1的全面分子理解 DNA损伤中的信号转导，并发现PARP-1信号如何在轻微或 严重的DNA损伤，从而阻止神经细胞死亡，但增强肿瘤细胞死亡。如果成功，则 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 癌症或中风的治疗。此外，对监管网络的全面了解 PARP-1信号也可能导致开发新的治疗策略来治疗人类 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.