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Genes Jul 2021The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. They serve as the site of rRNA synthesis and processing, and... (Review)
Review
The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. They serve as the site of rRNA synthesis and processing, and ribosome assembly. There are 400-600 copies of rRNA genes (rDNA) in human cells and their highly repetitive and transcribed nature poses a challenge for DNA repair and replication machineries. It is only in the last 7 years that the DNA damage response and processes of DNA repair at the rDNA repeats have been recognized to be unique and distinct from the classic response to DNA damage in the nucleoplasm. In the last decade, the nucleolus has also emerged as a central hub for coordinating responses to stress via sequestering tumor suppressors, DNA repair and cell cycle factors until they are required for their functional role in the nucleoplasm. In this review, we focus on features of the rDNA repeats that make them highly vulnerable to DNA damage and the mechanisms by which rDNA damage is repaired. We highlight the molecular consequences of rDNA damage including activation of the nucleolar DNA damage response, which is emerging as a unique response that can be exploited in anti-cancer therapy. In this review, we focus on CX-5461, a novel inhibitor of Pol I transcription that induces the nucleolar DNA damage response and is showing increasing promise in clinical investigations.
Topics: Antineoplastic Agents; Cell Nucleolus; DNA Damage; DNA, Ribosomal; Humans; Neoplasms
PubMed: 34440328
DOI: 10.3390/genes12081156 -
Cancer Science Apr 2012Cell growth demands new protein synthesis, which requires nucleolar ribosomal functions. Ribosome biogenesis consumes a large proportion of the cell's resources and... (Review)
Review
Cell growth demands new protein synthesis, which requires nucleolar ribosomal functions. Ribosome biogenesis consumes a large proportion of the cell's resources and energy, and so is tightly regulated through an intricate signaling network to guarantee fidelity. Thus, events that impair ribosome biogenesis cause nucleolar stress. In response to this stress, several nucleolar ribosomal proteins (RPs) translocate to the nucleoplasm and bind to MDM2. MDM2-mediated ubiquitination and degradation of the tumor suppressor p53 is then blocked, resulting in p53 accumulation and the induction of p53-dependent cell cycle arrest and apoptosis. Nucleolar stress is therefore a quality control surveillance mechanism that monitors the synthesis and assembly of the rRNA and protein components of ribosomes. Although nucleolar stress signaling pathways have been extensively analyzed, critical questions remain about their regulatory mechanisms. For example, how do RPs translocate from the nucleolus to the nucleoplasm to exert their functions, and do these p53-regulating RPs influence the prognosis of human cancer patients? Our laboratory recently identified the nucleolar protein PICT1 as a novel regulator of nucleolar stress. PICT1 sequesters the ribosomal protein RPL11 in the nucleolus, preventing it from binding to MDM2. MDM2 is then free to degrade p53, favoring tumor cell growth. Accordingly, the level of PICT1 in a tumor is becoming a useful prognostic marker for human cancers. This review summarizes the evidence that links nucleolar stress to tumorigenesis, and casts PICT1 as an oncogenic player in human cancer biology.
Topics: Cell Cycle; Cell Nucleolus; Gene Expression Regulation; Humans; Neoplasms; Proto-Oncogene Proteins c-mdm2; RNA, Ribosomal; Ribosomal Proteins; Ribosomes; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitination
PubMed: 22320853
DOI: 10.1111/j.1349-7006.2012.02219.x -
Nucleus (Austin, Tex.) May 2016The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and... (Review)
Review
The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a "nucleoplasmic reticulum," into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer's disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer's disease-related neurodegeneration in vivo. Additionally, we demonstrated that proper function of the nucleoskeleton is required for survival of adult neurons and maintaining genomic architecture. Here, we elaborate on the significance of these findings in regard to pathological states and physiological aging, and discuss cellular causes and consequences of nuclear envelope invagination.
Topics: Alzheimer Disease; Animals; Humans; Lamin Type B; Mutation; Neurons; Nuclear Lamina; Tauopathies
PubMed: 27167528
DOI: 10.1080/19491034.2016.1183859 -
ELife Nov 2019Liquid-liquid phase separation (LLPS) has been recognized as one of the key cellular organizing principles and was shown to be responsible for formation of membrane-less...
Liquid-liquid phase separation (LLPS) has been recognized as one of the key cellular organizing principles and was shown to be responsible for formation of membrane-less organelles such as nucleoli. Although nucleoli were found to behave like liquid droplets, many ramifications of LLPS including nucleolar dynamics and interactions with the surrounding liquid remain to be revealed. Here, we study the motion of human nucleoli , while monitoring the shape of the nucleolus-nucleoplasm interface. We reveal two types of nucleolar pair dynamics: an unexpected correlated motion prior to coalescence and an independent motion otherwise. This surprising kinetics leads to a nucleolar volume distribution, [Formula: see text], unaccounted for by any current theory. Moreover, we find that nucleolus-nucleoplasm interface is maintained by ATP-dependent processes and susceptible to changes in chromatin transcription and packing. Our results extend and enrich the LLPS framework by showing the impact of the surrounding nucleoplasm on nucleoli in living cells.
Topics: Adenosine Triphosphate; Cell Nucleolus; Cell Nucleus; Chromatin; Humans; Kinetics; Nuclear Proteins
PubMed: 31769409
DOI: 10.7554/eLife.47533 -
Frontiers in Plant Science 2022The existence of the nucleus distinguishes prokaryotes and eukaryotes. Apart from containing most of the genetic material, the nucleus possesses several nuclear bodies... (Review)
Review
The existence of the nucleus distinguishes prokaryotes and eukaryotes. Apart from containing most of the genetic material, the nucleus possesses several nuclear bodies composed of protein and RNA molecules. The nucleus is separated from the cytoplasm by a double membrane, regulating the trafficking of molecules in- and outwards. Here, we investigate the composition and function of the different plant nuclear bodies and molecular clues involved in nuclear trafficking. The behavior of the nucleolus, Cajal bodies, dicing bodies, nuclear speckles, cyclophilin-containing bodies, photobodies and DNA damage foci is analyzed in response to different abiotic stresses. Furthermore, we research the literature to collect the different protein localization signals that rule nucleocytoplasmic trafficking. These signals include the different types of nuclear localization signals (NLSs) for nuclear import, and the nuclear export signals (NESs) for nuclear export. In contrast to these unidirectional-movement signals, the existence of nucleocytoplasmic shuttling signals (NSSs) allows bidirectional movement through the nuclear envelope. Likewise, nucleolar signals are also described, which mainly include the nucleolar localization signals (NoLSs) controlling nucleolar import. In contrast, few examples of nucleolar export signals, called nucleoplasmic localization signals (NpLSs) or nucleolar export signals (NoESs), have been reported. The existence of consensus sequences for these localization signals led to the generation of prediction tools, allowing the detection of these signals from an amino acid sequence. Additionally, the effect of high temperatures as well as different post-translational modifications in nuclear and nucleolar import and export is discussed.
PubMed: 36082296
DOI: 10.3389/fpls.2022.984163 -
Biochimica Et Biophysica Acta.... Feb 2022The general segregation of a molecular class, lipids, from the pathways of cellular communication, via endo-membranes, has resulted in the over-simplification and... (Review)
Review
The general segregation of a molecular class, lipids, from the pathways of cellular communication, via endo-membranes, has resulted in the over-simplification and misconceptions in deciphering cell signalling mechanisms. Mechanisms in signal transduction and protein activation require targeting of proteins to membranous compartments with a specific localised morphology and dynamics that are dependent on their lipid composition. Many posttranslational events define cellular behaviours and without the active role of membranous compartments these events lead to various dysregulations of the signalling pathways. We summarise the key findings, using tools such as the rapalogue dimerisation, in the structural roles and signalling of the inter-related phosphoinositide lipids and their derivative, diacylglycerol, in the regulation of nuclear envelope biogenesis and other subcellular compartments such as the nucleoplasmic reticulum.
Topics: Cell Communication; Membrane Lipids; Nuclear Envelope; Phosphatidylinositols; Signal Transduction
PubMed: 34547252
DOI: 10.1016/j.bbamem.2021.183780 -
Frontiers in Plant Science 2021The shape of plant nuclei varies among different species, tissues, and cell types. In seedlings, nuclei in meristems and guard cells are nearly spherical, whereas those... (Review)
Review
The shape of plant nuclei varies among different species, tissues, and cell types. In seedlings, nuclei in meristems and guard cells are nearly spherical, whereas those of epidermal cells in differentiated tissues are elongated spindle-shaped. The vegetative nuclei in pollen grains are irregularly shaped in angiosperms. In the past few decades, it has been revealed that several nuclear envelope (NE) proteins play the main role in the regulation of the nuclear shape in plants. Some plant NE proteins that regulate nuclear shape are also involved in nuclear or cellular functions, such as nuclear migration, maintenance of chromatin structure, gene expression, calcium and reactive oxygen species signaling, plant growth, reproduction, and plant immunity. The shape of the nucleus has been assessed both by labeling internal components (for instance chromatin) and by labeling membranes, including the NE or endoplasmic reticulum in interphase cells and viral-infected cells of plants. Changes in NE are correlated with the formation of invaginations of the NE, collectively called the nucleoplasmic reticulum. In this review, what is known and what is unknown about nuclear shape determination are presented, and the physiological significance of the control of the nuclear shape in plants is discussed.
PubMed: 34177991
DOI: 10.3389/fpls.2021.673905 -
Nucleus (Austin, Tex.) Jan 2018The nucleoporin Nup98 has been linked to the regulation of transcription and RNA metabolism, but the mechanisms by which Nup98 contributes to these processes remains... (Review)
Review
The nucleoporin Nup98 has been linked to the regulation of transcription and RNA metabolism, but the mechanisms by which Nup98 contributes to these processes remains largely undefined. Recently, we uncovered interactions between Nup98 and several DExH/D-box proteins (DBPs), a protein family well-known for modulating gene expression and RNA metabolism. Analysis of Nup98 and one of these DBPs, DHX9, showed that they directly interact, their association is facilitated by RNA, and Nup98 binding stimulates DHX9 ATPase activity. Furthermore, these proteins were dependent on one another for their proper association with a subset of gene loci to control transcription and modulate mRNA splicing. On the basis of these observations, we proposed that Nup98 functions to regulate DHX9 activity within the nucleoplasm. Since Nup98 is associated with several DBPs, regulation of DHX9 by Nup98 may represent a paradigm for understanding how Nup98, and possibly other FG-Nup proteins, could direct the diverse cellular activities of multiple DBPs.
Topics: Cell Nucleus; DEAD-box RNA Helicases; Gene Expression Regulation; Humans; Nuclear Pore Complex Proteins; RNA
PubMed: 28934014
DOI: 10.1080/19491034.2017.1364826 -
Cell Reports Aug 2023The nucleolus is the most prominent membraneless organelle within the nucleus. How the nucleolar structure is regulated is poorly understood. Here, we identified two...
The nucleolus is the most prominent membraneless organelle within the nucleus. How the nucleolar structure is regulated is poorly understood. Here, we identified two types of nucleoli in C. elegans. Type I nucleoli are spherical and do not have visible nucleolar vacuoles (NoVs), and rRNA transcription and processing factors are evenly distributed throughout the nucleolus. Type II nucleoli contain vacuoles, and rRNA transcription and processing factors exclusively accumulate in the periphery rim. The NoV contains nucleoplasmic proteins and is capable of exchanging contents with the nucleoplasm. The high-order structure of the nucleolus is dynamically regulated in C. elegans. Faithful rRNA processing is important to prohibit NoVs. The depletion of 27SA rRNA processing factors resulted in NoV formation. The inhibition of RNA polymerase I (RNAPI) transcription and depletion of two conserved nucleolar factors, nucleolin and fibrillarin, prohibits the formation of NoVs. This finding provides a mechanism to coordinate structure maintenance and gene expression.
Topics: Animals; Caenorhabditis elegans; Nuclear Proteins; Vacuoles; Cell Nucleolus; Cell Nucleus; RNA, Ribosomal
PubMed: 37537842
DOI: 10.1016/j.celrep.2023.112915 -
Frontiers in Cell and Developmental... 2022The nucleus harbours numerous protein subdomains and condensates that regulate chromatin organization, gene expression and genomic stress. A novel nuclear subdomain that... (Review)
Review
The nucleus harbours numerous protein subdomains and condensates that regulate chromatin organization, gene expression and genomic stress. A novel nuclear subdomain that is formed following exposure of cells to excess fatty acids is the nuclear lipid droplet (nLD), which is composed of a neutral lipid core surrounded by a phospholipid monolayer and associated regulatory and lipid biosynthetic enzymes. While structurally resembling cytoplasmic LDs, nLDs are formed by distinct but poorly understood mechanisms that involve the emergence of lipid droplets from the lumen of the nucleoplasmic reticulum and lipid synthesis. Luminal lipid droplets that emerge into the nucleoplasm do so at regions of the inner nuclear membrane that become enriched in promyelocytic leukemia (PML) protein. The resulting nLDs that retain PML on their surface are termed lipid-associated PML structures (LAPS), and are distinct from canonical PML nuclear bodies (NB) as they lack key proteins and modifications associated with these NBs. PML is a key regulator of nuclear signaling events and PML NBs are sites of gene regulation and post-translational modification of transcription factors. Therefore, the subfraction of nLDs that form LAPS could regulate lipid stress responses through their recruitment and retention of the PML protein. Both nLDs and LAPS have lipid biosynthetic enzymes on their surface suggesting they are active sites for nuclear phospholipid and triacylglycerol synthesis as well as global lipid regulation. In this review we have summarized the current understanding of nLD and LAPS biogenesis in different cell types, their structure and composition relative to other PML-associated cellular structures, and their role in coordinating a nuclear response to cellular overload of fatty acids.
PubMed: 35178392
DOI: 10.3389/fcell.2022.837406