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Proteomic Analysis of the Downstream Signaling Network of PARP1
Biochemistry ( IF 2.9 ) Pub Date : 2018-01-19 00:00:00 , DOI: 10.1021/acs.biochem.7b01022 Yuanli Zhen 1 , Yonghao Yu 1
Biochemistry ( IF 2.9 ) Pub Date : 2018-01-19 00:00:00 , DOI: 10.1021/acs.biochem.7b01022 Yuanli Zhen 1 , Yonghao Yu 1
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Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses. It is catalyzed by a class of enzymes known as poly-ADP-ribose polymerases (PARPs). In particular, PARP1 is a nuclear protein that is activated upon sensing nicked DNA. Once activated, PARP1 is responsible for the synthesis of a large number of PARylated proteins and initiation of the DNA damage response mechanisms. This observation provided the rationale for developing PARP1 inhibitors for the treatment of human malignancies. Indeed, three PARP1 inhibitors (Olaparib, Rucaparib, and Niraparib) have recently been approved by the Food and Drug Administration for the treatment of ovarian cancer. Moreover, in 2017, both Olaparib and Niraparib have also been approved for the treatment of fallopian tube cancer and primary peritoneal cancer. Despite this very exciting progress in the clinic, the basic signaling mechanism that connects PARP1 to a diverse array of biological processes is still poorly understood. This is, in large part, due to the inherent technical difficulty associated with the analysis of protein PARylation, which is a low-abundance, labile, and heterogeneous PTM. The study of PARylation has been greatly facilitated by the recent advances in mass spectrometry-based proteomic technologies tailored to the analysis of this modification. In this Perspective, we discuss these breakthroughs, including their technical development, and applications that provide a global view of the many biological processes regulated by this important protein modification.
中文翻译：
PARP1下游信号网络的蛋白质组学分析
聚ADP核糖基化（PARylation）是一种蛋白质翻译后修饰（PTM），在许多与细胞应激反应相关的生物学过程中都至关重要。它被称为聚ADP核糖聚合酶（PARP）的一类酶催化。特别是，PARP1是一种核蛋白，在检测到有缺口的DNA后会被激活。激活后，PARP1负责大量PARylated蛋白的合成和DNA损伤反应机制的启动。该观察结果为开发用于治疗人类恶性肿瘤的PARP1抑制剂提供了理论依据。实际上，食品和药物管理局最近批准了三种PARP1抑制剂（奥拉帕里布，鲁卡帕里布和尼拉帕里布）用于治疗卵巢癌。此外，在2017年，Olaparib和Niraparib均已被批准用于治疗输卵管癌和原发性腹膜癌。尽管在临床上取得了令人振奋的进展，但仍不太了解将PARP1连接到各种生物过程的基本信号传导机制。这在很大程度上是由于与蛋白质PARylation分析相关的固有技术难度，这是一种低丰度，不稳定和异质的PTM。基于质谱的蛋白质组学技术的最新进展极大地促进了PARylation的研究，该技术专门用于分析这种修饰。在此观点中，我们将讨论这些突破，包括其技术发展，
更新日期：2018-01-19
中文翻译：
PARP1下游信号网络的蛋白质组学分析
聚ADP核糖基化（PARylation）是一种蛋白质翻译后修饰（PTM），在许多与细胞应激反应相关的生物学过程中都至关重要。它被称为聚ADP核糖聚合酶（PARP）的一类酶催化。特别是，PARP1是一种核蛋白，在检测到有缺口的DNA后会被激活。激活后，PARP1负责大量PARylated蛋白的合成和DNA损伤反应机制的启动。该观察结果为开发用于治疗人类恶性肿瘤的PARP1抑制剂提供了理论依据。实际上，食品和药物管理局最近批准了三种PARP1抑制剂（奥拉帕里布，鲁卡帕里布和尼拉帕里布）用于治疗卵巢癌。此外，在2017年，Olaparib和Niraparib均已被批准用于治疗输卵管癌和原发性腹膜癌。尽管在临床上取得了令人振奋的进展，但仍不太了解将PARP1连接到各种生物过程的基本信号传导机制。这在很大程度上是由于与蛋白质PARylation分析相关的固有技术难度，这是一种低丰度，不稳定和异质的PTM。基于质谱的蛋白质组学技术的最新进展极大地促进了PARylation的研究，该技术专门用于分析这种修饰。在此观点中，我们将讨论这些突破，包括其技术发展，
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