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

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对组成性表达的核酶多聚(ADP-核糖)聚合酶1(PARP)的催化激活。这种激活有很多目的，从如果损伤可以修复的话，保护细胞，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弊大于利。消除或细胞死亡的过程可以遵循多种途径；我们在NSERC的支持下的工作和其他许多人的工作表明，PARP与两条主要的死亡途径有关，即细胞凋亡和坏死。我们假设这种酶的各种活性包括其产物：ADP-核糖的聚合体，在细胞死亡过程中被死亡相关的蛋白酶裂解，以及它与不同的细胞伙伴蛋白的相互作用，控制着细胞死亡或坏死的决定。 该项目的具体目标是确定是否： 1)在细胞死亡过程中产生的PARP及其片段通过与不同的细胞伙伴相互作用来控制不同的细胞死亡模式。 2)PARP作为一种使ADP-核糖产物聚合并引起细胞内酸化以响应DNA损伤的酶，可通过其酶活性影响死亡事件。 3)PARP与RNA裂解酶DICER-1协同作用，通过影响自噬产生成熟的microRNA或PARP，自噬是一种有利于生存的过程，可以影响细胞死亡的方式。 这一计划的长期目标是了解PARP如何通过其各种活动来确定细胞自身毁灭的最终旅程，以造福于身体的其他部分。

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.