Department of Biology, University of Konstanz, 78467 Konstanz, Germany.
Nucleic Acids Res. 2021 Sep 7;49(15):8432-8448. doi: 10.1093/nar/gkab618.
Poly(ADP-ribosyl)ation (PARylation) is a multifaceted post-translational modification, carried out by poly(ADP-ribosyl)transferases (poly-ARTs, PARPs), which play essential roles in (patho-) physiology, as well as cancer therapy. Using NAD+ as a substrate, acceptors, such as proteins and nucleic acids, can be modified with either single ADP-ribose units or polymers, varying considerably in length and branching. Recently, the importance of PAR structural heterogeneity with regards to chain length and branching came into focus. Here, we provide a concise overview on the current knowledge of the biochemical and physiological significance of such differently structured PAR. There is increasing evidence revealing that PAR's structural diversity influences the binding characteristics of its readers, PAR catabolism, and the dynamics of biomolecular condensates. Thereby, it shapes various cellular processes, such as DNA damage response and cell cycle regulation. Contrary to the knowledge on the consequences of PAR's structural diversity, insight into its determinants is just emerging, pointing to specific roles of different PARP members and accessory factors. In the future, it will be interesting to study the interplay with other post-translational modifications, the contribution of natural PARP variants, and the regulatory role of accessory molecules. This has the exciting potential for new therapeutic approaches, with the targeted modulation and tuning of PARPs' enzymatic functions, rather than their complete inhibition, as a central premise.
聚（ADP-核糖）化（PARylation）是一种多方面的翻译后修饰，由聚（ADP-核糖）转移酶（poly-ARTs，PARPs）执行，它们在（病理）生理学以及癌症治疗中发挥着重要作用。PARPs 使用 NAD+ 作为底物，可将单个 ADP-核糖单位或聚合物修饰到蛋白质和核酸等受体上，其长度和分支变化很大。最近，PAR 结构异质性在链长和分支方面的重要性引起了关注。在这里，我们简要概述了这种不同结构 PAR 的生化和生理意义的最新知识。越来越多的证据表明，PAR 的结构多样性会影响其结合特性、PAR 代谢和生物分子凝聚物的动力学。从而影响各种细胞过程，如 DNA 损伤反应和细胞周期调控。与 PAR 结构多样性的后果知识相反，其决定因素的认识才刚刚开始，这指向了不同 PARP 成员和辅助因子的特定作用。未来，研究与其他翻译后修饰的相互作用、天然 PARP 变体的贡献以及辅助分子的调节作用将很有趣。这为新的治疗方法提供了令人兴奋的潜力，靶向调节和调整 PARPs 的酶功能，而不是完全抑制它们，是一个核心前提。
