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8 pages, 238 KiB

Open AccessEditorial

Nucleolar Organization and Functions in Health and Disease

by Ursula Stochaj and Stephanie C. Weber

Cells 2020, 9(3), 526; https://doi.org/10.3390/cells9030526 - 25 Feb 2020

Cited by 16 | Viewed by 5315

Abstract

The nucleolus is a prominent, membraneless compartment found within the nucleus of eukaryotic cells. It forms around ribosomal RNA (rRNA) genes, where it coordinates the transcription, processing, and packaging of rRNA to produce ribosomal subunits. Recent efforts to characterize the biophysical properties of [...] Read more.

The nucleolus is a prominent, membraneless compartment found within the nucleus of eukaryotic cells. It forms around ribosomal RNA (rRNA) genes, where it coordinates the transcription, processing, and packaging of rRNA to produce ribosomal subunits. Recent efforts to characterize the biophysical properties of the nucleolus have transformed our understanding of the assembly and organization of this dynamic compartment. Indeed, soluble macromolecules condense from the nucleoplasm to form nucleoli through a process called liquid–liquid phase separation. Individual nucleolar components rapidly exchange with the nucleoplasm and separate within the nucleolus itself to form distinct subcompartments. In addition to its essential role in ribosome biogenesis, the nucleolus regulates many aspects of cell physiology, including genome organization, stress responses, senescence and lifespan. Consequently, the nucleolus is implicated in several human diseases, such as Hutchinson–Gilford progeria syndrome, Diamond–Blackfan anemia, and various forms of cancer. This Special Issue highlights new insights into the physical and molecular mechanisms that control the architecture and diverse functions of the nucleolus, and how they break down in disease. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

Research

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22 pages, 8302 KiB

Open AccessArticle

DNA Damage Changes Distribution Pattern and Levels of HP1 Protein Isoforms in the Nucleolus and Increases Phosphorylation of HP1β-Ser88

by Soňa Legartová, Gabriela Lochmanová, Zbyněk Zdráhal, Stanislav Kozubek, Jiří Šponer, Miroslav Krepl, Pavlína Pokorná and Eva Bártová

Cells 2019, 8(9), 1097; https://doi.org/10.3390/cells8091097 - 17 Sep 2019

Cited by 8 | Viewed by 5817

Abstract

The family of heterochromatin protein 1 (HP1) isoforms is essential for chromatin packaging, regulation of gene expression, and repair of damaged DNA. Here we document that γ-radiation reduced the number of HP1α-positive foci, but not HP1β and HP1γ foci, located in the vicinity [...] Read more.

The family of heterochromatin protein 1 (HP1) isoforms is essential for chromatin packaging, regulation of gene expression, and repair of damaged DNA. Here we document that γ-radiation reduced the number of HP1α-positive foci, but not HP1β and HP1γ foci, located in the vicinity of the fibrillarin-positive region of the nucleolus. The additional analysis confirmed that γ-radiation has the ability to significantly decrease the level of HP1α in rDNA promoter and rDNA encoding 28S rRNA. By mass spectrometry, we showed that treatment by γ-rays enhanced the HP1β serine 88 phosphorylation (S88ph), but other analyzed modifications of HP1β, including S161ph/Y163ph, S171ph, and S174ph, were not changed in cells exposed to γ-rays or treated by the HDAC inhibitor (HDACi). Interestingly, a combination of HDACi and γ-radiation increased the level of HP1α and HP1γ. The level of HP1β remained identical before and after the HDACi/γ-rays treatment, but HDACi strengthened HP1β interaction with the KRAB-associated protein 1 (KAP1) protein. Conversely, HP1γ did not interact with KAP1, although approximately 40% of HP1γ foci co-localized with accumulated KAP1. Especially HP1γ foci at the periphery of nucleoli were mostly absent of KAP1. Together, DNA damage changed the morphology, levels, and interaction properties of HP1 isoforms. Also, γ-irradiation-induced hyperphosphorylation of the HP1β protein; thus, HP1β-S88ph could be considered as an important marker of DNA damage. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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19 pages, 12087 KiB

Open AccessArticle

The Intrinsically Disordered C-Terminal Domain Triggers Nucleolar Localization and Function Switch of PARN in Response to DNA Damage

by Tian-Li Duan, Guang-Jun He, Li-Dan Hu and Yong-Bin Yan

Cells 2019, 8(8), 836; https://doi.org/10.3390/cells8080836 - 5 Aug 2019

Cited by 9 | Viewed by 4287

Abstract

Poly(A)-specific ribonuclease (PARN), a multifunctional multi-domain deadenylase, is crucial to the regulation of mRNA turnover and the maturation of various non-coding RNAs. Despite extensive studies of the well-folding domains responsible for PARN catalysis, the structure and function of the C-terminal domain (CTD) remains [...] Read more.

Poly(A)-specific ribonuclease (PARN), a multifunctional multi-domain deadenylase, is crucial to the regulation of mRNA turnover and the maturation of various non-coding RNAs. Despite extensive studies of the well-folding domains responsible for PARN catalysis, the structure and function of the C-terminal domain (CTD) remains elusive. PARN is a cytoplasm–nucleus shuttle protein with concentrated nucleolar distribution. Here, we identify the nuclear and nucleolar localization signals in the CTD of PARN. Spectroscopic studies indicated that PARN-CTD is intrinsically disordered with loosely packed local structures/tertiary structure. Phosphorylation-mimic mutation S557D disrupted the local structure and facilitated the binding of the CTD with the well-folded domains, with no impact on PARN deadenylase activity. Under normal conditions, the nucleolus-residing PARN recruited CBP80 into the nucleoli to repress its deadenylase activity, while DNA damage-induced phosphorylation of PARN-S557 expelled CBP80 from the nucleoli to discharge activity inhibition and attracted nucleoplasm-located CstF-50 into the nucleoli to activate deadenylation. The structure switch-induced function switch of PARN reshaped the profile of small nuclear non-coding RNAs to respond to DNA damage. Our findings highlight that the structure switch of the CTD induced by posttranslational modifications redefines the subset of binding partners, and thereby the RNA targets in the nucleoli. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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15 pages, 3292 KiB

Open AccessArticle

Physicochemical Properties of Nucleoli in Live Cells Analyzed by Label-Free Optical Diffraction Tomography

by Tae-Keun Kim, Byong-Wook Lee, Fumihiko Fujii, Jun Ki Kim and Chan-Gi Pack

Cells 2019, 8(7), 699; https://doi.org/10.3390/cells8070699 - 10 Jul 2019

Cited by 26 | Viewed by 5211

Abstract

The cell nucleus is three-dimensionally and dynamically organized by nuclear components with high molecular density, such as chromatin and nuclear bodies. The structure and functions of these components are represented by the diffusion and interaction of related factors. Recent studies suggest that the [...] Read more.

The cell nucleus is three-dimensionally and dynamically organized by nuclear components with high molecular density, such as chromatin and nuclear bodies. The structure and functions of these components are represented by the diffusion and interaction of related factors. Recent studies suggest that the nucleolus can be assessed using various protein probes, as the probes are highly mobile in this organelle, although it is known that they have a densely packed structure. However, physicochemical properties of the nucleolus itself, such as molecular density and volume when cellular conditions are changed, are not yet fully understood. In this study, physical parameters such as the refractive index (RI) and volume of the nucleoli in addition to the diffusion coefficient (D) of fluorescent probe protein inside the nucleolus are quantified and compared by combining label-free optical diffraction tomography (ODT) with confocal laser scanning microscopy (CLSM)-based fluorescence correlation spectroscopy (FCS). 3D evaluation of RI values and corresponding RI images of nucleoli in live HeLa cells successfully demonstrated varying various physiological conditions. Our complimentary method suggests that physical property of the nucleolus in live cell is sensitive to ATP depletion and transcriptional inhibition, while it is insensitive to hyper osmotic pressure when compared with the cytoplasm and nucleoplasm. The result demonstrates that the nucleolus has unique physicochemical properties when compared with other cellular components. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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14 pages, 2491 KiB

Open AccessArticle

Hyperosmotic Stress Response Memory is Modulated by Gene Positioning in Yeast

by Zacchari Ben Meriem, Yasmine Khalil, Pascal Hersen and Emmanuelle Fabre

Cells 2019, 8(6), 582; https://doi.org/10.3390/cells8060582 - 13 Jun 2019

Cited by 13 | Viewed by 4293

Abstract

Cellular memory is a critical ability that allows microorganisms to adapt to potentially detrimental environmental fluctuations. In the unicellular eukaryote Saccharomyces cerevisiae, cellular memory can take the form of faster or slower responses within the cell population to repeated stresses. Using microfluidics [...] Read more.

Cellular memory is a critical ability that allows microorganisms to adapt to potentially detrimental environmental fluctuations. In the unicellular eukaryote Saccharomyces cerevisiae, cellular memory can take the form of faster or slower responses within the cell population to repeated stresses. Using microfluidics and fluorescence time-lapse microscopy, we studied how yeast responds to short, pulsed hyperosmotic stresses at the single-cell level by analyzing the dynamic behavior of the stress-responsive STL1 promoter (pSTL1) fused to a fluorescent reporter. We established that pSTL1 exhibits variable successive activation patterns following two repeated short stresses. Despite this variability, most cells exhibited a memory of the first stress as decreased pSTL1 activity in response to the second stress. Notably, we showed that genomic location is important for the memory effect, since displacement of the promoter to a pericentromeric chromatin domain decreased the transcriptional strength of pSTL1 and led to a loss of memory. This study provides a quantitative description of a cellular memory that includes single-cell variability and highlights the contribution of chromatin structure to stress memory. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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19 pages, 4837 KiB

Open AccessArticle

An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress

by Nada Essawy, Camille Samson, Ambre Petitalot, Sophie Moog, Anne Bigot, Isaline Herrada, Agathe Marcelot, Ana-Andreea Arteni, Catherine Coirault and Sophie Zinn-Justin

Cells 2019, 8(6), 570; https://doi.org/10.3390/cells8060570 - 10 Jun 2019

Cited by 16 | Viewed by 6677

Abstract

Emerin is a nuclear envelope protein that contributes to genome organization and cell mechanics. Through its N-terminal LAP2-emerin-MAN1 (LEM)-domain, emerin interacts with the DNA-binding protein barrier-to-autointegration (BAF). Emerin also binds to members of the linker of the nucleoskeleton and cytoskeleton (LINC) complex. Mutations [...] Read more.

Emerin is a nuclear envelope protein that contributes to genome organization and cell mechanics. Through its N-terminal LAP2-emerin-MAN1 (LEM)-domain, emerin interacts with the DNA-binding protein barrier-to-autointegration (BAF). Emerin also binds to members of the linker of the nucleoskeleton and cytoskeleton (LINC) complex. Mutations in the gene encoding emerin are responsible for the majority of cases of X-linked Emery-Dreifuss muscular dystrophy (X-EDMD). Most of these mutations lead to an absence of emerin. A few missense and short deletion mutations in the disordered region of emerin are also associated with X-EDMD. More recently, missense and short deletion mutations P22L, ∆K37 and T43I were discovered in emerin LEM-domain, associated with isolated atrial cardiac defects (ACD). Here we reveal which defects, at both the molecular and cellular levels, are elicited by these LEM-domain mutations. Whereas ΔK37 mutation impaired the correct folding of the LEM-domain, P22L and T43I had no impact on the 3D structure of emerin. Surprisingly, all three mutants bound to BAF, albeit with a weaker affinity in the case of ΔK37. In human myofibroblasts derived from a patient’s fibroblasts, emerin ∆K37 was correctly localized at the inner nuclear membrane, but was present at a significantly lower level, indicating that this mutant is abnormally degraded. Moreover, SUN2 was reduced, and these cells were defective in producing actin stress fibers when grown on a stiff substrate and after cyclic stretches. Altogether, our data suggest that the main effect of mutation ΔK37 is to perturb emerin function within the LINC complex in response to mechanical stress. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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Review

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20 pages, 886 KiB

Open AccessReview

Therapeutic Approaches Targeting Nucleolus in Cancer

by Pietro Carotenuto, Annalisa Pecoraro, Gaetano Palma, Giulia Russo and Annapina Russo

Cells 2019, 8(9), 1090; https://doi.org/10.3390/cells8091090 - 16 Sep 2019

Cited by 60 | Viewed by 5989

Abstract

The nucleolus is a distinct sub-cellular compartment structure in the nucleus. First observed more than 200 years ago, the nucleolus is detectable by microscopy in eukaryotic cells and visible during the interphase as a sub-nuclear structure immersed in the nucleoplasm, from which it [...] Read more.

The nucleolus is a distinct sub-cellular compartment structure in the nucleus. First observed more than 200 years ago, the nucleolus is detectable by microscopy in eukaryotic cells and visible during the interphase as a sub-nuclear structure immersed in the nucleoplasm, from which it is not separated from any membrane. A huge number of studies, spanning over a century, have identified ribosome biogenesis as the main function of the nucleolus. Recently, novel functions, independent from ribosome biogenesis, have been proposed by several proteomic, genomic, and functional studies. Several works have confirmed the non-canonical role for nucleoli in regulating important cellular processes including genome stability, cell-cycle control, the cellular senescence, stress responses, and biogenesis of ribonucleoprotein particles (RNPs). Many authors have shown that both canonical and non-canonical functions of the nucleolus are associated with several cancer-related processes. The association between the nucleolus and cancer, first proposed by cytological and histopathological studies showing that the number and shape of nucleoli are commonly altered in almost any type of cancer, has been confirmed at the molecular level by several authors who demonstrated that numerous mechanisms occurring in the nucleolus are altered in tumors. Recently, therapeutic approaches targeting the nucleolus in cancer have started to be considered as an emerging “hallmark” of cancer and several therapeutic interventions have been developed. This review proposes an up-to-date overview of available strategies targeting the nucleolus, focusing on novel targeted therapeutic approaches. Finally, a target-based classification of currently available treatment will be proposed. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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18 pages, 1736 KiB

Open AccessReview

Recent Advances on the Structure and Function of RNA Acetyltransferase Kre33/NAT10

by Sophie Sleiman and Francois Dragon

Cells 2019, 8(9), 1035; https://doi.org/10.3390/cells8091035 - 5 Sep 2019

Cited by 29 | Viewed by 7730

Abstract

Ribosome biogenesis is one of the most energy demanding processes in the cell. In eukaryotes, the main steps of this process occur in the nucleolus and include pre-ribosomal RNA (pre-rRNA) processing, post-transcriptional modifications, and assembly of many non-ribosomal factors and ribosomal proteins in [...] Read more.

Ribosome biogenesis is one of the most energy demanding processes in the cell. In eukaryotes, the main steps of this process occur in the nucleolus and include pre-ribosomal RNA (pre-rRNA) processing, post-transcriptional modifications, and assembly of many non-ribosomal factors and ribosomal proteins in order to form mature and functional ribosomes. In yeast and humans, the nucleolar RNA acetyltransferase Kre33/NAT10 participates in different maturation events, such as acetylation and processing of 18S rRNA, and assembly of the 40S ribosomal subunit. Here, we review the structural and functional features of Kre33/NAT10 RNA acetyltransferase, and we underscore the importance of this enzyme in ribosome biogenesis, as well as in acetylation of non-ribosomal targets. We also report on the role of human NAT10 in Hutchinson–Gilford progeria syndrome. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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19 pages, 3304 KiB

Open AccessReview

The Nucleolus: A Multiphase Condensate Balancing Ribosome Synthesis and Translational Capacity in Health, Aging and Ribosomopathies

by Carl C. Correll, Jiri Bartek and Miroslav Dundr

Cells 2019, 8(8), 869; https://doi.org/10.3390/cells8080869 - 10 Aug 2019

Cited by 76 | Viewed by 11356

Abstract

The nucleolus is the largest membrane-less structure in the eukaryotic nucleus. It is involved in the biogenesis of ribosomes, essential macromolecular machines responsible for synthesizing all proteins required by the cell. The assembly of ribosomes is evolutionarily conserved and is the most energy-consuming [...] Read more.

The nucleolus is the largest membrane-less structure in the eukaryotic nucleus. It is involved in the biogenesis of ribosomes, essential macromolecular machines responsible for synthesizing all proteins required by the cell. The assembly of ribosomes is evolutionarily conserved and is the most energy-consuming cellular process needed for cell growth, proliferation, and homeostasis. Despite the significance of this process, the intricate pathophysiological relationship between the nucleolus and protein synthesis has only recently begun to emerge. Here, we provide perspective on new principles governing nucleolar formation and the resulting multiphase organization driven by liquid-liquid phase separation. With recent advances in the structural analysis of ribosome formation, we highlight the current understanding of the step-wise assembly of pre-ribosomal subunits and the quality control required for proper function. Finally, we address how aging affects ribosome genesis and how genetic defects in ribosome formation cause ribosomopathies, complex diseases with a predisposition to cancer. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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22 pages, 1936 KiB

Open AccessReview

Nucleolar and Ribosomal DNA Structure under Stress: Yeast Lessons for Aging and Cancer

by Emiliano Matos-Perdomo and Félix Machín

Cells 2019, 8(8), 779; https://doi.org/10.3390/cells8080779 - 26 Jul 2019

Cited by 32 | Viewed by 8630

Abstract

Once thought a mere ribosome factory, the nucleolus has been viewed in recent years as an extremely sensitive gauge of diverse cellular stresses. Emerging concepts in nucleolar biology include the nucleolar stress response (NSR), whereby a series of cell insults have a special [...] Read more.

Once thought a mere ribosome factory, the nucleolus has been viewed in recent years as an extremely sensitive gauge of diverse cellular stresses. Emerging concepts in nucleolar biology include the nucleolar stress response (NSR), whereby a series of cell insults have a special impact on the nucleolus. These insults include, among others, ultra-violet radiation (UV), nutrient deprivation, hypoxia and thermal stress. While these stresses might influence nucleolar biology directly or indirectly, other perturbances whose origin resides in the nucleolar biology also trigger nucleolar and systemic stress responses. Among the latter, we find mutations in nucleolar and ribosomal proteins, ribosomal RNA (rRNA) processing inhibitors and ribosomal DNA (rDNA) transcription inhibition. The p53 protein also mediates NSR, leading ultimately to cell cycle arrest, apoptosis, senescence or differentiation. Hence, NSR is gaining importance in cancer biology. The nucleolar size and ribosome biogenesis, and how they connect with the Target of Rapamycin (TOR) signalling pathway, are also becoming important in the biology of aging and cancer. Simple model organisms like the budding yeast Saccharomyces cerevisiae, easy to manipulate genetically, are useful in order to study nucleolar and rDNA structure and their relationship with stress. In this review, we summarize the most important findings related to this topic. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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16 pages, 1730 KiB

Open AccessReview

Long Noncoding RNAs and Stress Response in the Nucleolus

by Sergei A. Pirogov, Vladimir A. Gvozdev and Mikhail S. Klenov

Cells 2019, 8(7), 668; https://doi.org/10.3390/cells8070668 - 2 Jul 2019

Cited by 47 | Viewed by 6124

Abstract

Long noncoding RNAs (lncRNAs) perform diverse functions in the regulation of cellular processes. Here we consider a variety of lncRNAs found in the ribosome production center, the nucleolus, and focus on their role in the response to environmental stressors. Nucleolar lncRNAs ensure stress [...] Read more.

Long noncoding RNAs (lncRNAs) perform diverse functions in the regulation of cellular processes. Here we consider a variety of lncRNAs found in the ribosome production center, the nucleolus, and focus on their role in the response to environmental stressors. Nucleolar lncRNAs ensure stress adaptation by cessation of resource-intensive ribosomal RNA (rRNA) synthesis and by inducing the massive sequestration of proteins within the nucleolus. Different cell states like quiescence and cancer are also controlled by specific lncRNAs in the nucleolus. Taken together, recent findings allow us to consider lncRNAs as multifunctional regulators of nucleolar activities, which are responsive to various physiological conditions. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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20 pages, 1329 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Genome Organization in and around the Nucleolus

by Cristiana Bersaglieri and Raffaella Santoro

Cells 2019, 8(6), 579; https://doi.org/10.3390/cells8060579 - 12 Jun 2019

Cited by 80 | Viewed by 10966

Abstract

The nucleolus is the largest substructure in the nucleus, where ribosome biogenesis takes place, and forms around the nucleolar organizer regions (NORs) that comprise ribosomal RNA (rRNA) genes. Each cell contains hundreds of rRNA genes, which are organized in three distinct chromatin and [...] Read more.

The nucleolus is the largest substructure in the nucleus, where ribosome biogenesis takes place, and forms around the nucleolar organizer regions (NORs) that comprise ribosomal RNA (rRNA) genes. Each cell contains hundreds of rRNA genes, which are organized in three distinct chromatin and transcriptional states—silent, inactive and active. Increasing evidence indicates that the role of the nucleolus and rRNA genes goes beyond the control of ribosome biogenesis. Recent results highlighted the nucleolus as a compartment for the location and regulation of repressive genomic domains and, together with the nuclear lamina, represents the hub for the organization of the inactive heterochromatin. In this review, we aim to describe the crosstalk between the nucleolus and the rest of the genome and how distinct rRNA gene chromatin states affect nucleolus structure and are implicated in genome stability, genome architecture, and cell fate decision. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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13 pages, 1066 KiB

Open AccessReview

Nucleolar and Ribosomal Dysfunction—A Common Pathomechanism in Childhood Progerias?

by Tamara Phan, Fatima Khalid and Sebastian Iben

Cells 2019, 8(6), 534; https://doi.org/10.3390/cells8060534 - 4 Jun 2019

Cited by 9 | Viewed by 4737

Abstract

The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and most of the assembly and maturation processes of the ribosome occur co-transcriptionally. Therefore, disturbances in [...] Read more.

The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and most of the assembly and maturation processes of the ribosome occur co-transcriptionally. Therefore, disturbances in rRNA transcription and processing translate to ribosomal malfunction. Nucleolar malfunction has recently been described in the classical progeria of childhood, Hutchinson–Gilford syndrome (HGPS), which is characterized by severe signs of premature aging, including atherosclerosis, alopecia, and osteoporosis. A deregulated ribosomal biogenesis with enlarged nucleoli is not only characteristic for HGPS patients, but it is also found in the fibroblasts of “normal” aging individuals. Cockayne syndrome (CS) is also characterized by signs of premature aging, including the loss of subcutaneous fat, alopecia, and cataracts. It has been shown that all genes in which a mutation causes CS, are involved in rDNA transcription by RNA Pol I. A disturbed ribosomal biogenesis affects mitochondria and translates into ribosomes with a reduced translational fidelity that causes endoplasmic reticulum (ER) stress and apoptosis. Therefore, it is speculated that disease-causing disturbances in the process of ribosomal biogenesis may be more common than hitherto anticipated. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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22 pages, 1512 KiB

Open AccessReview

Nucleolar Structure and Function in Trypanosomatid Protozoa

by Santiago Martínez-Calvillo, Luis E. Florencio-Martínez and Tomás Nepomuceno-Mejía

Cells 2019, 8(5), 421; https://doi.org/10.3390/cells8050421 - 8 May 2019

Cited by 15 | Viewed by 12754

Abstract

The nucleolus is the conspicuous nuclear body where ribosomal RNA genes are transcribed by RNA polymerase I, pre-ribosomal RNA is processed, and ribosomal subunits are assembled. Other important functions have been attributed to the nucleolus over the years. Here we review the current [...] Read more.

The nucleolus is the conspicuous nuclear body where ribosomal RNA genes are transcribed by RNA polymerase I, pre-ribosomal RNA is processed, and ribosomal subunits are assembled. Other important functions have been attributed to the nucleolus over the years. Here we review the current knowledge about the structure and function of the nucleolus in the trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania ssp., which represent one of the earliest branching lineages among the eukaryotes. These protozoan parasites present a single nucleolus that is preserved throughout the closed nuclear division, and that seems to lack fibrillar centers. Trypanosomatids possess a relatively low number of rRNA genes, which encode rRNA molecules that contain large expansion segments, including several that are trypanosomatid-specific. Notably, the large subunit rRNA (28S-type) is fragmented into two large and four small rRNA species. Hence, compared to other organisms, the rRNA primary transcript requires additional processing steps in trypanosomatids. Accordingly, this group of parasites contains the highest number ever reported of snoRNAs that participate in rRNA processing. The number of modified rRNA nucleotides in trypanosomatids is also higher than in other organisms. Regarding the structure and biogenesis of the ribosomes, recent cryo-electron microscopy analyses have revealed several trypanosomatid-specific features that are discussed here. Additional functions of the nucleolus in trypanosomatids are also reviewed. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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16 pages, 1097 KiB

Open AccessReview

Proteins of the Nucleolus of Dictyostelium discoideum: Nucleolar Compartmentalization, Targeting Sequences, Protein Translocations and Binding Partners

by Danton H. O’Day

Cells 2019, 8(2), 167; https://doi.org/10.3390/cells8020167 - 17 Feb 2019

Cited by 5 | Viewed by 4306

Abstract

The nucleoli of Dictyostelium discoideum have a comparatively unique, non-canonical, localization adjacent to the inner nuclear membrane. The verified nucleolar proteins of this eukaryotic microbe are detailed while other potential proteins are introduced. Heat shock protein 32 (Hsp32), eukaryotic translation initiation factor 6 [...] Read more.

The nucleoli of Dictyostelium discoideum have a comparatively unique, non-canonical, localization adjacent to the inner nuclear membrane. The verified nucleolar proteins of this eukaryotic microbe are detailed while other potential proteins are introduced. Heat shock protein 32 (Hsp32), eukaryotic translation initiation factor 6 (eIF6), and tumour necrosis factor receptor-associated protein 1 (TRAP1) are essential for cell survival. NumA1, a breast cancer type 1 susceptibility protein-C Terminus domain-containing protein linked to cell cycle, functions in the regulation of nuclear number. The cell cycle checkpoint kinase 2 homologue forkhead-associated kinase A (FhkA) and BRG1-associated factor 60a homologue Snf12 are also discussed. While nucleoli appear homogeneous ultrastructurally, evidence for nucleolar subcompartments exists. Nucleolar localization sequences (NoLS) have been defined that target proteins to either the general nucleolar area or to a specific intranucleolar domain. Protein translocations during mitosis are protein-specific and support the multiple functions of the Dictyostelium nucleolus. To enrich the picture, binding partners of NumA1, the most well-characterized nucleolar protein, are examined: nucleolar Ca²⁺-binding protein 4a (CBP4a), nuclear puromycin-sensitive aminopeptidase A (PsaA) and Snf12. The role of Dictyostelium as a model for understanding the contribution of nucleolar proteins to various diseases and cellular stress is discussed throughout the review. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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15 pages, 3300 KiB

Open AccessReview

The Ribosome Biogenesis—Cancer Connection

by Marianna Penzo, Lorenzo Montanaro, Davide Treré and Massimo Derenzini

Cells 2019, 8(1), 55; https://doi.org/10.3390/cells8010055 - 15 Jan 2019

Cited by 159 | Viewed by 11521

Abstract

Multifaceted relations link ribosome biogenesis to cancer. Ribosome biogenesis takes place in the nucleolus. Clarifying the mechanisms involved in this nucleolar function and its relationship with cell proliferation: (1) allowed the understanding of the reasons for the nucleolar changes in cancer cells and [...] Read more.

Multifaceted relations link ribosome biogenesis to cancer. Ribosome biogenesis takes place in the nucleolus. Clarifying the mechanisms involved in this nucleolar function and its relationship with cell proliferation: (1) allowed the understanding of the reasons for the nucleolar changes in cancer cells and their exploitation in tumor pathology, (2) defined the importance of the inhibition of ribosome biogenesis in cancer chemotherapy and (3) focused the attention on alterations of ribosome biogenesis in the pathogenesis of cancer. This review summarizes the research milestones regarding these relevant relationships between ribosome biogenesis and cancer. The structure and function of the nucleolus will also be briefly described. Full article

(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)

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