PDF(Pubmed)
Abstract：
Poly(ADP-ribose) polymerases (PARPs) are critical to regulating cellular activities, such as the response to DNA damage and cell death. PARPs catalyze a reversible post-translational modification (PTM) in the form of mono- or poly(ADP-ribosyl)ation. This type of modification is known to form a ubiquitin-ADP-ribose (Ub-ADPR) conjugate that depends on the actions of Deltex family of E3 ubiquitin ligases (DTXs). In particular, DTXs add ubiquitin to the 3\'-OH of adenosine ribose\' in ADP-ribose, which effectively sequesters ubiquitin and impedes ubiquitin-dependent signaling. Previous work demonstrates DTX function for ubiquitination of protein-free ADPR, mono-ADP-ribosylated peptides, and ADP-ribosylated nucleic acids. However, the dynamics of DTX-mediated ubiquitination of poly(ADP-ribosyl)ation remains to be defined. Here we show that the ADPR ubiquitination function is not found in other PAR-binding E3 ligases and is conserved across DTX family members. Importantly, DTXs specifically target poly(ADP-ribose) chains for ubiquitination that can be cleaved by PARG, the primary eraser of poly(ADP-ribose), leaving the adenosine-terminal ADPR unit conjugated to ubiquitin. Our collective results demonstrate the DTXs\' specific ubiquitination of the adenosine terminus of poly(ADP-ribosyl)ation and suggest the unique Ub-ADPR conjugation process as a basis for PARP-DTX control of cellular activities.
摘要：
聚(ADP-核糖)聚合酶(PARP)是调节细胞活动的关键,例如对DNA损伤和细胞死亡的反应。PARP催化单-或聚(ADP-核糖基)形式的可逆翻译后修饰(PTM)。已知这种类型的修饰形成泛素-ADP-核糖（Ub-ADPR）缀合物，该缀合物取决于E3泛素连接酶（DTX）的Deltex家族的作用。特别是,DTX将泛素添加到ADP-核糖中腺苷核糖的3'-OH中，有效地隔离泛素并阻止泛素依赖性信号传导。先前的工作证明了DTX对无蛋白ADPR泛素化的功能，单-ADP-核糖基化肽，和ADP-核糖基化核酸。然而,DTX介导的聚（ADP-核糖基）泛素化的动力学仍有待定义。在这里，我们表明ADPR泛素化功能在其他PAR结合E3连接酶中未发现，并且在DTX家族成员中保守。重要的是,DTX特异性靶向聚（ADP-核糖）链用于泛素化，可被PARG裂解，聚(ADP-核糖)的初级橡皮擦，留下与泛素缀合的腺苷末端ADPR单元。我们的集体结果证明了多（ADP-核糖基）腺苷末端的DTX特异性泛素化，并表明独特的Ub-ADPR缀合过程是PARP-DTX控制细胞活性的基础。
