Role of poly(ADP-ribose) polymerase-1 in cell death

多聚腺苷二磷酸核糖聚合酶-1在细胞死亡中的作用 高等真核细胞对DNA损伤的最早反应之一是组成型表达的核酶聚（ADP-核糖）聚合酶-1（PARP）的催化活化。这种激活有许多目的，从保护细胞，如果损伤可以修复，但更重要的是，这种酶也有助于消除严重受损的细胞，因为这种受损和改变的细胞的生存可能对身体有害而非有益。消除或细胞死亡的过程可以遵循多种途径;我们的工作得到了NSERC的支持，许多其他人的工作表明PARP涉及两种主要的死亡途径，即凋亡和坏死。我们推测，决定死亡的细胞凋亡或坏死是由各种活动的这种酶，包括其产品：ADP-核糖的聚合物，其碎片的死亡相关的蛋白酶在细胞死亡和它的相互作用与不同的细胞伴侣蛋白。 该项目的具体目标是确定： 1)PARP及其在细胞死亡过程中产生的片段通过与不同细胞伴侣的相互作用控制不同的细胞死亡模式。 2)PARP作为一种酶，使ADP-核糖的产物聚合物，也引起细胞内酸化响应DNA损伤，可以通过其酶活性影响死亡事件。 3)PARP与RNA切割酶Dicer-1协同作用，Dicer-1通过其对自噬的影响产生成熟的microRNA或PARP，自噬是一种促生存过程，可以影响细胞死亡的模式。 该计划的长期目标是了解PARP及其各种活动如何能够确定细胞最终走向自身毁灭的旅程，以造福身体的其他部分。

Role of poly(ADP-ribose) polymerase-1 in cell death Among the earliest responses of higher eukaryotic cells to DNA damage is catalytic activation of a constitutively expressed nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP). This activation serves many purposes ranging from protecting the cells if the damage can be repaired, but more importantly this enzyme also helps in elimination of badly damaged cells because survival of such damaged and altered cells may be more harmful than good for the body. The process of elimination or cell death can follow variety of routes; and our work supported by NSERC and work of many others indicate that PARP is implicated in two major death routes, namely apoptosis and necrosis. We hypothesize that the decision to die by apoptosis or necrosis is controlled by various activities of this enzyme including its product: a polymer of ADP-ribose, its fragmentation by death-related proteases during cell death and its interaction with different cellular partner proteins. The specific objectives of the project are to determine whether: 1) PARP and its fragments created during cell death control different modes of cell death via interaction with different cellular partners. 2) PARP as an enzyme that makes the product polymer of ADP-ribose and also causes intracellular acidification in response to DNA damage can influence death events through its enzymatic activities. 3) PARP acts in concert with an RNA-cleaving enzyme Dicer-1 that creates mature microRNA or PARP via its influence on autophagy, a pro-survival process, can influence the mode of cell death. The long-term goal of this program is to understand how PARP with its various activities is able to determine the final journey of the cell to its own destruction for the benefit of rest of the body.