去乙酰化转移酶SIRT7的作用及机制研究进展

SIRT7是哺乳动物Sirtuins家族中的一员,定位于核仁,是一种高度特异性的H3K18Ac(组蛋白H3的乙酰化18位赖氨酸残基)去乙酰化酶。近年来的研究发现SIRT7可通过多种途径参与调控核糖体RNA转录、细胞代谢、细胞应激以及DNA损伤修复等生理过程。此外,SIRT7还与衰老、心脏疾病及脂肪肝等密切相关。特别是SIRT7在多种肿瘤如肝癌、胃癌、乳腺癌、膀胱癌、结直肠癌、胰腺癌和头颈鳞状细胞癌等发生发展中起着重要的调节作用。文中综述了SIRT7的细胞及分子生物学作用,并系统总结了其在人类疾病中的研究现状。     

细胞周期决定核糖体蛋白S6在真核细胞核仁中的聚积

核糖体蛋白S6（rpS6）是核糖体40S小亚基的核心组成蛋白之一。研究表明,rpS6可以通过核定位信号进入细胞核中,在核仁中参与核糖体的组装。在该研究中发现,rpS6在高等真核细胞核仁中的聚积与细胞周期有关,rpS6在S期中晚期开始在核仁中聚积,G2期含量达到最高,M期核仁分解时消失。推测,rpS6在核仁中的这种分布特性可能与核糖体的合成随细胞周期变化有关。     

核糖体合成调控蛋白RRS1的功能及其与疾病的关系

1999年,Tsuno等在酵母中发现了一个核糖体合成调控蛋白,命名为RRS1。在酵母中,RRS1是一个多功能的蛋白,与核糖体产物因子2相互作用,在25S r RNA成熟过程中起重要作用,并参与核糖体60S大亚基的生物合成。在哺乳动物细胞中,RRS1参与细胞周期中染色体在赤道板的聚集和端粒的聚集。RRS1在亨廷顿病等的发生中发挥着重要作用。我们简要概述RRS1的功能及其与疾病的关系。     

核仁蛋白质的定位、移位和核仁功能

核仁一直被认为只是核糖体合成和加工的场所,但是近年研究发现它具有其他功能.核仁是一个高度动态的亚细胞结构,通常情况下核仁蛋白质在核仁内外不断穿梭完成对于核糖体的运输.但在细胞应激反应时核仁成为细胞应激的感受器(cell stress sensor),核仁蛋白质在核仁内外的定位分布发生改变,同时伴随功能改变,介导细胞的应激反应.     

核糖体灭活蛋白在植物中的作用

植物核糖体灭活蛋白 (ribosome -inactivatingproteins ,RIPs)能够破坏真核或原核细胞的核糖体大亚基RNA ,使核糖体失活而不能与蛋白质合成过程中的延伸因子相结合 ,从而导致蛋白质合成受到抑制。不同的核糖体对不同RIPs的敏感性不同 ,RIPs对自体或异体核糖体的作用也有很大区别。RIPs对病毒有很强的抑制作用 ,并且有些RIPs表现出对某些真菌和昆虫的抗性 ,因此认为核糖体灭活蛋白在植物的防御反应中扮演重要角色。另外 ,RIPs还可能参与了细胞代谢、细胞死亡等生理调控过程。     

核仁应激损伤与热休克蛋白研究

核仁作为细胞核糖体生物合成的场所,在细胞的增殖、分化,以及衰老等生命活动中发挥重要作用。多种应激原可导致核仁结构及功能损伤。应激状态下,多种热休克蛋白向核仁移位以保护核仁损伤。深入探讨应激状态下核仁损伤及热休克蛋白保护核仁损伤的分子机制,是细脆生物学研究的重要内容。     

核糖体相关质量控制与核糖体自噬研究进展

细胞中蛋白质处于不断合成和降解的动态更新过程中,其稳态与细胞功能密切相关。细胞中存在多种蛋白质质量控制（protein quality control,PQC）机制来监测蛋白质合成和降解过程的异常,以确保蛋白质组的完整性和细胞适应性。核糖体是细胞内数量最多的细胞器,系细胞内蛋白质合成的主要场所。现已明确,核糖体相关质量控制（ribosome-associated quality control,RQC）与核糖体自噬能通过溶酶体依赖和非依赖途径调节细胞内核糖体数量及功能以维持蛋白质稳态,从而增强细胞在应激状态下的适应能力。RQC失调、核糖体自噬障碍则参与多种疾病的发生及发展过程,靶向RQC和核糖体自噬可能成为防治多种疾病的有效手段。本综述聚焦核糖体相关的PQC途径,并进一步讨论了它们在蛋白质稳态维持中的重要地位及其在人类疾病发生发展中的潜在作用。     

真核生物rRNA基因的转录调节

核糖体RNA(rRNA）基因的转录直接决定着细胞核糖体的生物发生,而后者与细胞的生长、增殖等行为相适应.研究发现,rRNA基因转录以RNA聚合酶Ⅰ（Pol Ⅰ）为核心,有多种因子参与,并受到多种调控因子的严密调节控制;各调控因子不仅均有自己特异的作用位点,而且又彼此关联、相辅相成.本文在简要介绍真核生物rRNA基因转录基本过程与涉及的主要因子的基础上,重点阐述了rRNA基因转录的主要调节方式,包括ERK、mTOR和JNK等信号转导通路对转录因子磷酸化的影响;转录因子的乙酰化;细胞周期相关因子和其它因子的多种作用方式等. 概括起来看,真核生物rRNA基因转录调节的核心机制是调节转录因子间及转录因子与DNA间的相互作用或影响染色质结构,从而实现对rRNA基因转录的调控,以满足特定生理/病理状况下细胞对rRNA量的要求.     

从基因组分析贾第虫的核糖体合成系统

为探讨贾第虫细胞核内核糖体合成系统,及与典型的真核生物有何差异,首先,确定在典型真核生物中参与核糖体合成的129条共有的保守蛋白,然后用这些蛋白搜索贾第虫基因组以调查它们在贾第虫中的直系同源蛋白的情况,以对贾第虫的核糖体合成系统作一了解。结果表明：贾第虫具有89条这些蛋白的直系同源蛋白,包括参与rRNA甲基化和假尿嘧啶化的蛋白复合体成员,以及存在于90S、40S和60S复合体中的蛋白。贾第虫的核糖体合成系统与典型的真核生物相似,但还有40条蛋白在贾第虫基因组中找不到同源蛋白。这意味着贾第虫的核糖体合成系统较典型的真核生物简单。贾第虫虽然没有核仁结构,但其核糖体亚基合成的途径和机制可能与真核细胞相似,参与的成分不同于无核仁结构的原核生物,可能相对简单。     

蚕豆根端细胞核中微核仁的研究

以蚕豆(Vicia faba)根端分生组织细胞为材料研究了微核仁的超微结构和细胞化学特点。结果表明;微核仁是直径0.3—0.5μm 的卵圆形或球形结构。常规染色时,微核仁与集缩染色质的电子密度相仿,但两者之间在结构上没有任何联系。细胞化学研究指出,微核仁含有 RNA 和蛋白质,其结构成分主要是与核仁颗粒组分十分相似的 RNP 颗粒。报道了植物细胞核中微核仁发生于核仁的过程并对微核仁的本质和功能进行了讨论。     

Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells

Ribosome biogenesis is an energy consuming process which takes place mainly in the nucleolus. By producing ribosomes to fuel protein synthesis, it is tightly connected with cell growth and cell cycle control. Perturbation of ribosome biogenesis leads to the activation of p53 tumor suppressor protein promoting processes like cell cycle arrest, apoptosis or senescence. This ribosome biogenesis stress pathway activates p53 through sequestration of MDM2 by a subset of ribosomal proteins (RPs), thereby stabilizing p53. Here, we identify human HEATR1, as a nucleolar protein which positively regulates ribosomal RNA (rRNA) synthesis. Downregulation of HEATR1 resulted in cell cycle arrest in a manner dependent on p53. Moreover, depletion of HEATR1 also caused disruption of nucleolar structure and activated the ribosomal biogenesis stress pathway – RPL5 / RPL11 dependent stabilization and activation of p53. These findings reveal an important role for HEATR1 in ribosome biogenesis and further support the concept that perturbation of ribosome biosynthesis results in p53-dependent cell cycle checkpoint activation, with implications for human pathologies including cancer.     

The multifunctional nucleolus

The nucleolus is a distinct subnuclear compartment that was first observed more than 200 years ago. Nucleoli assemble around the tandemly repeated ribosomal DNA gene clusters and 28S, 18S and 5.8S ribosomal RNAs (rRNAs) are transcribed as a single precursor, which is processed and assembled with the 5S rRNA into ribosome subunits. Although the nucleolus is primarily associated with ribosome biogenesis, several lines of evidence now show that it has additional functions. Some of these functions, such as regulation of mitosis, cell-cycle progression and proliferation, many forms of stress response and biogenesis of multiple ribonucleoprotein particles, will be discussed, as will the relation of the nucleolus to human diseases.     

Nucleolus: the fascinating nuclear body

Nucleoli are the prominent contrasted structures of the cell nucleus. In the nucleolus, ribosomal RNAs are synthesized, processed and assembled with ribosomal proteins. RNA polymerase I synthesizes the ribosomal RNAs and this activity is cell cycle regulated. The nucleolus reveals the functional organization of the nucleus in which the compartmentation of the different steps of ribosome biogenesis is observed whereas the nucleolar machineries are in permanent exchange with the nucleoplasm and other nuclear bodies. After mitosis, nucleolar assembly is a time and space regulated process controlled by the cell cycle. In addition, by generating a large volume in the nucleus with apparently no RNA polymerase II activity, the nucleolus creates a domain of retention/sequestration of molecules normally active outside the nucleolus. Viruses interact with the nucleolus and recruit nucleolar proteins to facilitate virus replication. The nucleolus is also a sensor of stress due to the redistribution of the ribosomal proteins in the nucleoplasm by nucleolus disruption. The nucleolus plays several crucial functions in the nucleus: in addition to its function as ribosome factory of the cells it is a multifunctional nuclear domain, and nucleolar activity is linked with several pathologies. Perspectives on the evolution of this research area are proposed.     

Early rRNA processing is a stress-dependent regulatory event whose inhibition maintains nucleolar integrity

The production of ribosomes is an energy-intensive process owing to the intricacy of these massive macromolecular machines. Each human ribosome contains 80 ribosomal proteins and four non-coding RNAs. Accurate assembly requires precise regulation of protein and RNA subunits. In response to stress, the integrated stress response (ISR) rapidly inhibits global translation. How rRNA is coordinately regulated with the rapid inhibition of ribosomal protein synthesis is not known. Here, we show that stress specifically inhibits the first step of rRNA processing. Unprocessed rRNA is stored within the nucleolus, and when stress resolves, it re-enters the ribosome biogenesis pathway. Retention of unprocessed rRNA within the nucleolus aids in the maintenance of this organelle. This response is independent of the ISR or inhibition of cellular translation but is independently regulated. Failure to coordinately control ribosomal protein translation and rRNA production results in nucleolar fragmentation. Our study unveils how the rapid translational shut-off in response to stress coordinates with rRNA synthesis production to maintain nucleolar integrity.