ADP-ribosylation is a prominent and versatile post-translational modification, which regulates a diverse set of cellular processes. Poly-ADP-ribose (PAR) is synthesised by the poly-ADP-ribosyltransferases PARP1, PARP2, tankyrase (TNKS), and tankyrase 2 (TNKS2), all of which are linked to human disease. PARP1/2 inhibitors have entered the clinic to target cancers with deficiencies in DNA damage repair. Conversely, tankyrase inhibitors have continued to face obstacles on their way to clinical use, largely owing to our limited knowledge of their molecular impacts on tankyrase and effector pathways, and linked concerns around their tolerability. Whilst detailed structure-function studies have revealed a comprehensive picture of PARP1/2 regulation, our mechanistic understanding of the tankyrases lags behind, and thereby our appreciation of the molecular consequences of tankyrase inhibition. Despite large differences in their architecture and cellular contexts, recent structure-function work has revealed striking parallels in the regulatory principles that govern these enzymes. This includes low basal activity, activation by intra- or inter-molecular assembly, negative feedback regulation by auto-PARylation, and allosteric communication. Here we compare these poly-ADP-ribosyltransferases and point towards emerging parallels and open questions, whose pursuit will inform future drug development efforts.

中文翻译：

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PARP1/2 和 tankyrase 的调节：新兴的相似之处。


ADP-核糖基化是一种突出且多功能的翻译后修饰，可调节一组不同的细胞过程。多聚 ADP 核糖 （PAR） 由多聚 ADP 核糖基转移酶 PARP1、PARP2、tankyrase （TNKS） 和 tankyrase 2 （TNKS2） 合成，所有这些酶都与人类疾病有关。PARP1/2 抑制剂已进入临床，靶向 DNA 损伤修复缺陷的癌症。相反，tankyrase 抑制剂在临床使用过程中继续面临障碍，这主要是由于我们对它们对 tankyrase 和效应子途径的分子影响了解有限，并且对其耐受性的担忧相关。虽然详细的结构-功能研究揭示了 PARP1/2 调节的全面情况，但我们对 tankyrase 的机制理解滞后，因此我们对 tankyrase 抑制的分子后果的理解滞后。尽管它们的结构和细胞环境存在巨大差异，但最近的结构-功能研究揭示了控制这些酶的调节原则的惊人相似之处。这包括低基础活性、分子内或分子间组装的激活、自体 PARylation 的负反馈调节和变构通讯。在这里，我们比较了这些多聚 ADP-核糖基转移酶，并指出了新出现的相似之处和悬而未决的问题，这些问题的追求将为未来的药物开发工作提供信息。