Poly(ADP-Ribose) polymerase 1 (PARP-1) regulates ribosomal biogenesis in Drosophila nucleoli.
Poly(ADP-Ribose) polymerase 1 (PARP-1) regulates ribosomal biogenesis in Drosophila nucleoli.
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DOI：
10.1371/journal.pgen.1002442
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发表时间：
2012-01
期刊：
影响因子：
4.5
通讯作者：
Tulin AV
中科院分区：
文献类型：
--
作者：
Boamah EK;Kotova E;Garabedian M;Jarnik M;Tulin AV
聚(ADP-核糖)聚合酶1(PARP1)是一种核蛋白，它利用NAD合成聚(AD-Pribose)(PADPr)，导致受体蛋白的自我修饰和修饰。大量的PARP1和pADPr(高达50%)定位于核仁，核仁是一种亚核细胞器，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。利用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功能。我们的分析表明，PARP1酶活性的破坏导致了核仁的解体和核仁特异蛋白的异常定位。此外，PARP1突变体增加了rRNA中间体的积累，降低了核糖体水平。综上所述，我们的数据表明，PARP1的酶活性是将核仁蛋白靶向前体rRNA附近所必需的；因此，PARP1控制着前体rRNA的加工、转录后修饰和核糖体前组装。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，从而影响核糖体的生物发生。核糖体组装主要发生在亚核细胞器核仁中。在核仁中，核糖体组装成一个多聚体复合体，由rRNA和核糖体蛋白组成。虽然人们对核糖体及其功能了解很多，但对促进这些多聚体蛋白质复合体在核仁中组装的机制知之甚少。在这里，我们提供的证据表明，核蛋白PARP1，主要以其DNA损伤修复和转录活动而闻名，也在核糖体的组装中发挥关键作用。利用果蝇模型系统，我们表明PARP1在核仁中的定位影响核仁活动，如rRNA加工和核糖体生物发生。我们发现，当PARP1活性被破坏时，在野生型条件下正常共定位的核仁蛋白分散到核质中，没有表现出任何共定位。我们还表明，一些对rRNA加工至关重要的核仁蛋白质也与pADPr相互作用，这使这些蛋白质与前体rRNA保持近距离。当PARP1活性被破坏时，我们观察到前体rRNA积累和伴随而来的核糖体水平下降。综上所述，我们的数据表明了PARP1的一种新的活性，并突出了与核仁中的核糖体生物发生相关的潜在机制。
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. Ribosome assembly happens primarily in the subnuclear organelle nucleolus. In the nucleolus, ribosomes are assembled into a multmeric complex, composed of rRNA and ribosomal proteins. Although a lot is known about ribosomes and how they function, very little is known about the mechanism that facilitates the assembly of these multimeric protein complexes in the nucleolus. Here, we provide evidence that a nuclear protein, PARP1, primarily known for its DNA damage repair and transcriptional activities, also plays a critical role in the assembly of ribosomes. Using the Drosophila model system, we show that PARP1 localization within the nucleolus impacts such nucleolar activities as rRNA processing and ribosome biogenesis. We show that, when PARP1 activity is disrupted, nucleolar proteins that normally co-localize under wild-type conditions disperse into the nucleoplasm and do not show any co-localization. We also show that some nucleolar proteins, essential for rRNA processing, also interact with pADPr, which keeps these proteins close to precursor rRNA. When PARP1 activity was disrupted, we observed precursors rRNA accumulation and a concomitant decrease in the levels of ribosomes. Together, our data suggest a novel activity for PARP1 and highlight a potential mechanism associated with ribosome biogenesis in the nucleolus.
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