scholarly journals Nucleolar Organization and Functions in Health and Disease

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 526 ◽  
Author(s):  
Ursula Stochaj ◽  
Stephanie C. Weber
Keyword(s):  
Stress Responses ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Rrna Genes ◽  
Cell Physiology ◽  
Ribosomal Subunits ◽  
Diamond Blackfan Anemia ◽  
Health And Disease ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

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.

Eukaryotic protein uS19: a component of the decoding site of ribosomes and a player in human diseases

2021 ◽  
Vol 478 (5) ◽  
pp. 997-1008
Author(s):  
Dmitri Graifer ◽  
Galina Karpova
Keyword(s):  
Ribosome Biogenesis ◽  
Lymphocytic Leukemia ◽  
Human Diseases ◽  
Tumor Suppressor P53 ◽  
Translational Fidelity ◽  
Gene Encoding ◽  
Ribosomal Subunits ◽  
Translational Machinery ◽  
Diamond Blackfan Anemia ◽  
Ribosomal Function

Proteins belonging to the universal ribosomal protein (rp) uS19 family are constituents of small ribosomal subunits, and their conserved globular parts are involved in the formation of the head of these subunits. The eukaryotic rp uS19 (previously known as S15) comprises a C-terminal extension that has no homology in the bacterial counterparts. This extension is directly implicated in the formation of the ribosomal decoding site and thereby affects translational fidelity in a manner that has no analogy in bacterial ribosomes. Another eukaryote-specific feature of rp uS19 is its essential participance in the 40S subunit maturation due to the interactions with the subunit assembly factors required for the nuclear exit of pre-40S particles. Beyond properties related to the translation machinery, eukaryotic rp uS19 has an extra-ribosomal function concerned with its direct involvement in the regulation of the activity of an important tumor suppressor p53 in the Mdm2/Mdmx-p53 pathway. Mutations in the RPS15 gene encoding rp uS19 are linked to diseases (Diamond Blackfan anemia, chronic lymphocytic leukemia and Parkinson's disease) caused either by defects in the ribosome biogenesis or disturbances in the functioning of ribosomes containing mutant rp uS19, likely due to the changed translational fidelity. Here, we review currently available data on the involvement of rp uS19 in the operation of the translational machinery and in the maturation of 40S subunits, on its extra-ribosomal function, and on relationships between mutations in the RPS15 gene and certain human diseases.

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

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1035 ◽  
Author(s):  
Sophie Sleiman ◽  
Francois Dragon
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
40S Ribosomal Subunit ◽  
Functional Features ◽  
And Function ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Nucleolar Rna

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.

scholarly journals Nop53p is a novel nucleolar 60S ribosomal subunit biogenesis protein

2005 ◽  
Vol 388 (3) ◽  
pp. 819-826 ◽  
Author(s):  
Yaroslav SYDORSKYY ◽  
David J. DILWORTH ◽  
Brendan HALLORAN ◽  
Eugene C. YI ◽  
Taras MAKHNEVYCH ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Rrna Genes ◽  
Ribosomal Subunits ◽  
Nuclear Compartment ◽  
Growth Defects ◽  
Polysome Profiling ◽  
Rrna Maturation ◽  
Polymerase I

Ribosome biogenesis in Saccharomyces cerevisiae occurs primarily in a specialized nuclear compartment termed the nucleolus within which the rRNA genes are transcribed by RNA polymerase I into a large 35 S rRNA precursor. The ensuing association/dissociation and catalytic activity of numerous trans-acting protein factors, RNAs and ribosomal proteins ultimately leads to the maturation of the precursor rRNAs into 25, 5.8 and 18 S rRNAs and the formation of mature cytoplasmic 40 and 60 S ribosomal subunits. Although many components involved in ribosome biogenesis have been identified, our understanding of this essential cellular process remains limited. In the present study we demonstrate a crucial role for the previously uncharacterized nucleolar protein Nop53p (Ypl146p) in ribosome biogenesis. Specifically, Nop53p appears to be most important for biogenesis of the 60 S subunit. It physically interacts with rRNA processing factors, notably Cbf5p and Nop2p, and co-fractionates specifically with pre-60 S particles on sucrose gradients. Deletion or mutations within NOP53 cause significant growth defects and display significant 60 S subunit deficiencies, an imbalance in the 40 S:60 S ratio, as revealed by polysome profiling, and defects in progression beyond the 27 S stage of 25 S rRNA maturation during 60 S biogenesis.

scholarly journals Fanconi anemia A protein participates in nucleolar homeostasis maintenance and ribosome biogenesis

2021 ◽  
Vol 7 (1) ◽  
pp. eabb5414
Author(s):  
Anna Gueiderikh ◽  
Frédérique Maczkowiak-Chartois ◽  
Guillaume Rouvet ◽  
Sylvie Souquère-Besse ◽  
Sébastien Apcher ◽  
...  
Keyword(s):  
Dna Damage ◽  
Fanconi Anemia ◽  
Stress Responses ◽  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Loss Of Function ◽  
Independent Manner ◽  
Ribosomal Subunits ◽  
Nucleolar Proteins ◽  
Nucleolar Stress

Fanconi anemia (FA), the most common inherited bone marrow failure and leukemia predisposition syndrome, is generally attributed to alterations in DNA damage responses due to the loss of function of the DNA repair and replication rescue activities of the FANC pathway. Here, we report that FANCA deficiency, whose inactivation has been identified in two-thirds of FA patients, is associated with nucleolar homeostasis loss, mislocalization of key nucleolar proteins, including nucleolin (NCL) and nucleophosmin 1 (NPM1), as well as alterations in ribosome biogenesis and protein synthesis. FANCA coimmunoprecipitates with NCL and NPM1 in a FANCcore complex–independent manner and, unique among the FANCcore complex proteins, associates with ribosomal subunits, influencing the stoichiometry of the translational machineries. In conclusion, we have identified unexpected nucleolar and translational consequences specifically associated with FANCA deficiency that appears to be involved in both DNA damage and nucleolar stress responses, challenging current hypothesis on FA physiopathology.

scholarly journals GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease

2021 ◽  
Vol 22 (24) ◽  
pp. 13387
Author(s):  
Hanne Leysen ◽  
Deborah Walter ◽  
Bregje Christiaenssen ◽  
Romi Vandoren ◽  
İrem Harputluoğlu ◽  
...  
Keyword(s):  
Cell Surface ◽  
Stress Responses ◽  
Expression Patterns ◽  
Surface Membrane ◽  
Therapeutic Targets ◽  
Cell Surface Receptors ◽  
Dna Integrity ◽  
Cell Physiology ◽  
Surface Receptors ◽  
Health And Disease

GPCRs arguably represent the most effective current therapeutic targets for a plethora of diseases. GPCRs also possess a pivotal role in the regulation of the physiological balance between healthy and pathological conditions; thus, their importance in systems biology cannot be underestimated. The molecular diversity of GPCR signaling systems is likely to be closely associated with disease-associated changes in organismal tissue complexity and compartmentalization, thus enabling a nuanced GPCR-based capacity to interdict multiple disease pathomechanisms at a systemic level. GPCRs have been long considered as controllers of communication between tissues and cells. This communication involves the ligand-mediated control of cell surface receptors that then direct their stimuli to impact cell physiology. Given the tremendous success of GPCRs as therapeutic targets, considerable focus has been placed on the ability of these therapeutics to modulate diseases by acting at cell surface receptors. In the past decade, however, attention has focused upon how stable multiprotein GPCR superstructures, termed receptorsomes, both at the cell surface membrane and in the intracellular domain dictate and condition long-term GPCR activities associated with the regulation of protein expression patterns, cellular stress responses and DNA integrity management. The ability of these receptorsomes (often in the absence of typical cell surface ligands) to control complex cellular activities implicates them as key controllers of the functional balance between health and disease. A greater understanding of this function of GPCRs is likely to significantly augment our ability to further employ these proteins in a multitude of diseases.

scholarly journals Impaired ribosome biogenesis in Diamond-Blackfan anemia

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1275-1283 ◽  
Author(s):  
Valérie Choesmel ◽  
Daniel Bacqueville ◽  
Jacques Rouquette ◽  
Jacqueline Noaillac-Depeyre ◽  
Sébastien Fribourg ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
18S Rrna ◽  
Ribosomal Subunit ◽  
Rrna Synthesis ◽  
Rrna Processing ◽  
Gene Encoding ◽  
Ribosomal Subunits ◽  
Diamond Blackfan Anemia ◽  
Nucleolar Organization ◽  
Ribosomal Protein S19

Abstract The gene encoding the ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia. The consequence of these mutations on the onset of the disease remains obscure. Here, we show that RPS19 plays an essential role in biogenesis of the 40S small ribosomal subunit in human cells. Knockdown of RPS19 expression by siRNAs impairs 18S rRNA synthesis and formation of 40S subunits and induces apoptosis in HeLa cells. Pre-rRNA processing is altered, which leads to an arrest in the maturation of precursors to the 18S rRNA. Under these conditions, pre-40S particles are not exported to the cytoplasm and accumulate in the nucleoplasm of the cells in perinuclear dots. Consistently, we find that ribosome biogenesis and nucleolar organization is altered in skin fibroblasts from DBA patients bearing mutations in the RPS19 gene. In addition, maturation of the 18S rRNA is also perturbed in cells from a patient bearing no RPS19-related mutation. These results support the hypothesis that DBA is directly related to a defect in ribosome biogenesis and indicate that yet to be discovered DBA-related genes may be involved in the synthesis of the ribosomal subunits.

scholarly journals Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 88 ◽  
Author(s):  
Katarzyna Piekarowicz ◽  
Magdalena Machowska ◽  
Volha Dzianisava ◽  
Ryszard Rzepecki
Keyword(s):  
Gene Therapy ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Genetic Diseases ◽  
Subcutaneous Fat ◽  
Current Status ◽  
Single Mutation ◽  
Lmna Gene ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is one of the most severe disorders among laminopathies—a heterogeneous group of genetic diseases with a molecular background based on mutations in the LMNA gene and genes coding for interacting proteins. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat, alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood. LMNA codes for two major, alternatively spliced transcripts, give rise to lamin A and lamin C proteins. Mutations in the LMNA gene alone, depending on the nature and location, may result in the expression of abnormal protein or loss of protein expression and cause at least 11 disease phenotypes, differing in severity and affected tissue. LMNA gene-related HGPS is caused by a single mutation in the LMNA gene in exon 11. The mutation c.1824C > T results in activation of the cryptic donor splice site, which leads to the synthesis of progerin protein lacking 50 amino acids. The accumulation of progerin is the reason for appearance of the phenotype. In this review, we discuss current knowledge on the molecular mechanisms underlying the development of HGPS and provide a critical analysis of current research trends in this field. We also discuss the mouse models available so far, the current status of treatment of the disease, and future prospects for the development of efficient therapies, including gene therapy for HGPS.

scholarly journals MicroRNAs and long non-coding RNAs as novel regulators of ribosome biogenesis

2020 ◽  
Vol 48 (2) ◽  
pp. 595-612 ◽  
Author(s):  
Mason A. McCool ◽  
Carson J. Bryant ◽  
Susan J. Baserga
Keyword(s):  
Protein Synthesis ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Ribosomal Subunits ◽  
Additional Layer ◽  
Disease Outcomes ◽  
A Cell ◽  
Non Coding Rnas ◽  
Higher Eukaryotes ◽  
Pathological Disease

Ribosome biogenesis is the fine-tuned, essential process that generates mature ribosomal subunits and ultimately enables all protein synthesis within a cell. Novel regulators of ribosome biogenesis continue to be discovered in higher eukaryotes. While many known regulatory factors are proteins or small nucleolar ribonucleoproteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) are emerging as a novel modulatory layer controlling ribosome production. Here, we summarize work uncovering non-coding RNAs (ncRNAs) as novel regulators of ribosome biogenesis and highlight their links to diseases of defective ribosome biogenesis. It is still unclear how many miRNAs or lncRNAs are involved in phenotypic or pathological disease outcomes caused by impaired ribosome production, as in the ribosomopathies, or by increased ribosome production, as in cancer. In time, we hypothesize that many more ncRNA regulators of ribosome biogenesis will be discovered, which will be followed by an effort to establish connections between disease pathologies and the molecular mechanisms of this additional layer of ribosome biogenesis control.

scholarly journals Effects of Simulated Microgravity on the Proteome and Secretome of the Polyextremotolerant Black Fungus Knufia chersonesos

2021 ◽  
Vol 12 ◽  
Author(s):  
Donatella Tesei ◽  
Abby J. Chiang ◽  
Markus Kalkum ◽  
Jason E. Stajich ◽  
Ganesh Babu Malli Mohan ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Simulated Microgravity ◽  
Outer Space ◽  
Extreme Environments ◽  
Cellular Level ◽  
Cell Physiology ◽  
Morphological Alterations ◽  
Translational Machinery ◽  
Black Fungi

Black fungi are a group of melanotic microfungi characterized by remarkable polyextremotolerance. Due to a broad ecological plasticity and adaptations at the cellular level, it is predicted that they may survive in a variety of extreme environments, including harsh niches on Earth and Mars, and in outer space. However, the molecular mechanisms aiding survival, especially in space, are yet to be fully elucidated. Based on these premises, the rock-inhabiting black fungus Knufia chersonesos (Wt) and its non-melanized mutant (Mut) were exposed to simulated microgravity—one of the prevalent features characterizing space conditions—by growing the cultures in high-aspect-ratio vessels (HARVs). Qualitative and quantitative proteomic analyses were performed on the mycelia and supernatant of culture medium (secretome) to assess alterations in cell physiology in response to low-shear simulated microgravity (LSSMG) and to ultimately evaluate the role of cell-wall melanization in stress survival. Differential expression was observed for proteins involved in carbohydrate and lipid metabolic processes, transport, and ribosome biogenesis and translation via ribosomal translational machinery. However, no evidence of significant activation of stress components or starvation response was detected, except for the scytalone dehydratase, enzyme involved in the synthesis of dihydroxynaphthalene (DNH) melanin, which was found to be upregulated in the secretome of the wild type and downregulated in the mutant. Differences in protein modulation were observed between K. chersonesos Wt and Mut, with several proteins being downregulated under LSSMG in the Mut when compared to the Wt. Lastly, no major morphological alterations were observed following exposure to LSSMG. Similarly, the strains’ survivability was not negatively affected. This study is the first to characterize the response to simulated microgravity in black fungi, which might have implications on future astrobiological missions.

Astrocytes in health and disease

2007 ◽  
Vol 148 (15) ◽  
pp. 697-702 ◽  
Author(s):  
Marianna Murányi ◽  
Zsombor Lacza
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Free Radicals ◽  
Molecular Mechanisms ◽  
Neuronal Dysfunction ◽  
Supporting Cells ◽  
Neuronal Synapses ◽  
Health And Disease ◽  
Novel Targets ◽  
Therapeutic Tools

It is now known that astrocytes are not merely supporting cells but they also play an important role in neuronal funcions. Astrocytes tightly ensheat neuronal synapses and regulate the excitation of neurons by uptaking neurotransmitters; reglulate the cerebral blood flow, cerebral fluid volume and extracellular concentrations of ions. They also supply fuel in the form of lactate and provide free radical scavangers such as glutathione for active neurons. These facts indicate that impaired function of astrocytes may lead to neuronal dysfunction. After brain injury (stroke, trauma or tumors) astrocytes are swollen and release active molecules such as glutamate or free radicals resulting in neuronal dysfunction. Thus, investigation of the molecular mechanisms of astrocyte function may reveal novel targets for the development of therapeutic tools in neuronal diseases.

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