Mashimo Masato, Moss Joel
Rm. 6D05, Bldg. 10, MSC 1590, National Institutes of Health, Bethesda, MD 20892-1590; USA.
Curr Protein Pept Sci. 2016;17(7):633-640. doi: 10.2174/1389203717666160419144603.
Poly-ADP-ribosylation has been proposed to be a reversible protein modification, participating in diverse cellular functions including DNA repair, chromatin remodeling, genetic stability, mitosis, and cell death. Poly-ADP-ribosylation is initiated by the transfer of the ADP-ribose moiety of NAD+ primarily to the carboxyl groups of glutamate and aspartate and amino group of lysine residues in target proteins, followed by elongation of poly(ADP-ribose) (PAR) chains via α-O-glycosidic (C- 1"-C-2') ribose-ribose bonds. PAR consists of polymers of ADP-ribose (up to 200 units) with branching via α-O-glycosidic (C-1"'-C-2") ribose-ribose bonds. Further, the pyrophosphate group of each ADP-ribose has two negative charges. Therefore, in proteins modified by PAR, a complex structure with negative charges may lead to dynamic changes of functions. PAR formation is catalyzed by poly(ADP-ribose) polymerases (PARPs) and terminated by several types of enzymes with PAR-degrading activities; poly(ADP-ribose) glycohydrolase (PARG), ADP-ribosylacceptor hydrolase (ARH) 3, ARH1, and macrodomain-containing proteins. PARG has been thought to be primarily responsible for PAR degradation. In 2006, ARH3 was cloned and identified as another type of PAR-degrading protein. Although PAR-degrading activity of ARH3 is less than that of PARG, different mechanisms of PAR recognition and the cellular localization of ARH3 appear to be responsible for unique cellular roles of ARH3 involving PAR. In the present review, we focused on our findings regarding structure, biological properties, and cellular functions of ARH3. In addition, we describe the current knowledge of poly-ADP-ribosylation and cell death pathways regulated PARP1, PARG, and ARH3.
多聚 ADP - 核糖基化被认为是一种可逆的蛋白质修饰，参与多种细胞功能，包括 DNA 修复、染色质重塑、遗传稳定性、有丝分裂和细胞死亡。多聚 ADP - 核糖基化由 NAD⁺的 ADP - 核糖部分主要转移到靶蛋白中谷氨酸和天冬氨酸的羧基以及赖氨酸残基的氨基上起始，随后通过α - O - 糖苷键（C - 1" - C - 2'）核糖 - 核糖键延长多聚（ADP - 核糖）（PAR）链。PAR 由 ADP - 核糖聚合物（多达 200 个单位）组成，通过α - O - 糖苷键（C - 1"' - C - 2"）核糖 - 核糖键分支。此外，每个 ADP - 核糖的焦磷酸基团带有两个负电荷。因此，在被 PAR 修饰的蛋白质中，带有负电荷的复杂结构可能导致功能的动态变化。PAR 的形成由多聚（ADP - 核糖）聚合酶（PARP）催化，并由几种具有 PAR 降解活性的酶终止；多聚（ADP - 核糖）糖苷水解酶（PARG）、ADP - 核糖基受体水解酶（ARH）3、ARH1 和含宏结构域的蛋白质。PARG 一直被认为主要负责 PAR 的降解。2006 年，ARH3 被克隆并鉴定为另一种 PAR 降解蛋白。尽管 ARH3 的 PAR 降解活性低于 PARG，但 ARH3 对 PAR 的不同识别机制和细胞定位似乎负责 ARH3 涉及 PAR 的独特细胞作用。在本综述中，我们重点关注了关于 ARH3 的结构、生物学特性和细胞功能的研究结果。此外，我们描述了目前关于多聚 ADP - 核糖基化以及由 PARP1、PARG 和 ARH3 调节的细胞死亡途径的知识。
