Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2012 Jan;8(1):e1002442. doi: 10.1371/journal.pgen.1002442. Epub 2012 Jan 5.
Poly(ADP-ribose) polymerase 1 (PARP1), a nuclear protein, utilizes NAD to synthesize poly(AD-Pribose) (pADPr), resulting in both automodification and the modification of acceptor proteins. Substantial amounts of PARP1 and pADPr (up to 50%) are localized to the nucleolus, a subnuclear organelle known as a region for ribosome biogenesis and maturation. At present, the functional significance of PARP1 protein inside the nucleolus remains unclear. Using PARP1 mutants, we investigated the function of PARP1, pADPr, and PARP1-interacting proteins in the maintenance of nucleolus structure and functions. Our analysis shows that disruption of PARP1 enzymatic activity caused nucleolar disintegration and aberrant localization of nucleolar-specific proteins. Additionally, PARP1 mutants have increased accumulation of rRNA intermediates and a decrease in ribosome levels. Together, our data suggests that PARP1 enzymatic activity is required for targeting nucleolar proteins to the proximity of precursor rRNA; hence, PARP1 controls precursor rRNA processing, post-transcriptional modification, and pre-ribosome assembly. Based on these findings, we propose a model that explains how PARP1 activity impacts nucleolar functions and, consequently, ribosomal biogenesis.
聚（ADP-核糖）聚合酶 1（PARP1）是一种核蛋白，利用 NAD 合成聚（ADP-核糖）（pADPr），导致自身修饰和受体蛋白的修饰。大量的 PARP1 和 pADPr（高达 50%）定位于核仁，核仁是核仁是一个亚核细胞器，被称为核糖体生物发生和成熟的区域。目前，PARP1 蛋白在核仁内的功能意义尚不清楚。使用 PARP1 突变体，我们研究了 PARP1、pADPr 和 PARP1 相互作用蛋白在维持核仁结构和功能中的作用。我们的分析表明，PARP1 酶活性的破坏导致核仁解体和核仁特异性蛋白的异常定位。此外，PARP1 突变体中 rRNA 中间体的积累增加，核糖体水平降低。总之，我们的数据表明，PARP1 酶活性是将核仁蛋白靶向前体 rRNA 附近所必需的；因此，PARP1 控制前体 rRNA 加工、转录后修饰和前核糖体组装。基于这些发现，我们提出了一个模型，解释了 PARP1 活性如何影响核仁功能，进而影响核糖体生物发生。
