ADP-核糖基化是一种重要且多功能的翻译后修饰，可调节多种细胞过程。聚 ADP 核糖 (PAR) 由聚 ADP 核糖基转移酶 PARP1、PARP2、端锚聚合酶 (TNKS) 和端锚聚合酶 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，针对 DNA 损伤修复缺陷的癌症。相反，端锚聚合酶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其对端锚聚合酶和效应途径的分子影响的了解有限，并且对其耐受性存在担忧。虽然详细的结构-功能研究已经揭示了 PARP1/2 调节的全面图景，但我们对端锚聚合酶的机制理解滞后，因此我们对端锚聚合酶抑制的分子后果的认识滞后。尽管它们的结构和细胞环境存在很大差异，但最近的结构功能研究揭示了控制这些酶的调控原理惊人的相似之处。这包括低基础活性、分子内或分子间组装的激活、自动 PARylation 的负反馈调节以及变构通讯。在这里，我们比较这些聚 ADP-核糖基转移酶，并指出新出现的相似之处和悬而未决的问题，这些问题将为未来的药物开发工作提供信息。© 2024 作者。

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.© 2024 The Author(s).