Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
Proteomics Facility, Interdisciplinary Centre for Clinical Research (IZKF), Medical School, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
Sci Rep. 2018 Apr 30;8(1):6748. doi: 10.1038/s41598-018-25137-w.
Macrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP-ribosylation. TARG1/C6orf130 is a macrodomain protein that hydrolyzes mono-ADP-ribosylation and interacts with poly-ADP-ribose chains. Interactome analyses revealed that TARG1 binds strongly to ribosomes and proteins associated with rRNA processing and ribosomal assembly factors. TARG1 localized to transcriptionally active nucleoli, which occurred independently of ADP-ribose binding. TARG1 shuttled continuously between nucleoli and nucleoplasm. In response to DNA damage, which activates ARTD1/2 (PARP1/2) and promotes synthesis of poly-ADP-ribose chains, TARG1 re-localized to the nucleoplasm. This was dependent on the ability of TARG1 to bind to poly-ADP-ribose. These findings are consistent with the observed ability of TARG1 to competitively interact with RNA and PAR chains. We propose a nucleolar role of TARG1 in ribosome assembly or quality control that is stalled when TARG1 is re-located to sites of DNA damage.
宏结构域是与 ADP-核糖结合和周转相关的保守蛋白折叠。ADP-核糖基化是一种翻译后修饰，主要由细胞中的 ARTD（又名 PARP）酶催化。ARTD 将单个或多个 ADP-核糖单位转移到底物上，导致单或多 ADP-核糖基化。TARG1/C6orf130 是一种宏结构域蛋白，可水解单 ADP-核糖基化并与多 ADP-核糖链相互作用。相互作用分析表明，TARG1 强烈结合核糖体以及与 rRNA 加工和核糖体组装因子相关的蛋白质。TARG1 定位于转录活跃的核仁，这独立于 ADP-核糖结合。TARG1 在核仁与核质之间持续穿梭。当 DNA 损伤激活 ARTD1/2（PARP1/2）并促进多 ADP-核糖链的合成时，TARG1 重新定位到核质中。这依赖于 TARG1 结合多 ADP-核糖的能力。这些发现与观察到的 TARG1 与 RNA 和 PAR 链竞争相互作用的能力一致。我们提出 TARG1 在核仁中的核糖体组装或质量控制中的作用，当 TARG1 重新定位到 DNA 损伤部位时，该作用会停滞。
