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Cancer Research Jul 2022Ribosomes are a complex ensemble of rRNA and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is a multistep process that begins in the... (Review)
Review
Ribosomes are a complex ensemble of rRNA and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is a multistep process that begins in the nucleolus and concludes in the cytoplasm. The process is tightly controlled by multiple checkpoint and surveillance pathways. Perturbations in these checkpoints and pathways can lead to hyperactivation of ribosome biogenesis. Emerging evidence suggests that cancer cells harbor a specialized class of ribosomes (onco-ribosomes) that facilitates the oncogenic translation program, modulates cellular functions, and promotes metabolic rewiring. Mutations in ribosomal proteins, rRNA processing, and ribosome assembly factors result in ribosomopathies that are associated with an increased risk of developing malignancies. Recent studies have linked mutations in ribosomal proteins and aberrant ribosomes with poor prognosis, highlighting ribosome-targeted therapy as a promising approach for treating patients with cancer. Here, we summarize various aspects of dysregulation of ribosome biogenesis and the impact of resultant onco-ribosomes on malignant tumor behavior, therapeutic resistance, and clinical outcome. Ribosome biogenesis is a promising therapeutic target, and understanding the important determinants of this process will allow for improved and perhaps selective therapeutic strategies to target ribosome biosynthesis.
Topics: Cell Nucleolus; Drug Resistance, Neoplasm; Humans; Neoplasm Metastasis; Neoplasms; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 35303060
DOI: 10.1158/0008-5472.CAN-21-4087 -
Nature Feb 2023Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within...
Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus. This suggests that mutations in disordered proteins may alter condensate properties and function. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.
Topics: Humans; Arginine; Cell Nucleolus; HMGB1 Protein; Intrinsically Disordered Proteins; Syndrome; Frameshift Mutation; Phase Transition
PubMed: 36755093
DOI: 10.1038/s41586-022-05682-1 -
Genes & Development Jul 2022The nucleolus is best known for housing the highly ordered assembly line that produces ribosomal subunits. The >100 ribosome assembly factors in the nucleolus are... (Review)
Review
The nucleolus is best known for housing the highly ordered assembly line that produces ribosomal subunits. The >100 ribosome assembly factors in the nucleolus are thought to cycle between two states: an operative state (when integrated into subunit assembly intermediates) and a latent state (upon release from intermediates). Although it has become commonplace to refer to the nucleolus as "being a multilayered condensate," and this may be accurate for latent factors, there is little reason to think that such assertions pertain to the operative state of assembly factors.
Topics: Cell Nucleolus; RNA, Ribosomal
PubMed: 36342833
DOI: 10.1101/gad.349748.122 -
Aging May 2018
Topics: Animals; Cell Nucleolus; Humans; Mechanistic Target of Rapamycin Complex 1; Stress, Physiological
PubMed: 29788001
DOI: 10.18632/aging.101456 -
Cold Spring Harbor Perspectives in... Mar 2011When cells are observed by phase contrast microscopy, nucleoli are among the most conspicuous structures. The nucleolus was formally described between 1835 and 1839, but... (Review)
Review
When cells are observed by phase contrast microscopy, nucleoli are among the most conspicuous structures. The nucleolus was formally described between 1835 and 1839, but it was another century before it was discovered to be associated with a specific chromosomal locus, thus defining it as a cytogenetic entity. Nucleoli were first isolated in the 1950s, from starfish oocytes. Then, in the early 1960s, a boomlet of studies led to one of the epochal discoveries in the modern era of genetics and cell biology: that the nucleolus is the site of ribosomal RNA synthesis and nascent ribosome assembly. This epistemologically repositioned the nucleolus as not merely an aspect of nuclear anatomy but rather as a cytological manifestation of gene action-a major heuristic advance. Indeed, the finding that the nucleolus is the seat of ribosome production constitutes one of the most vivid confluences of form and function in the history of cell biology. This account presents the nucleolus in both historical and contemporary perspectives. The modern era has brought the unanticipated discovery that the nucleolus is plurifunctional, constituting a paradigm shift.
Topics: Cell Biology; Cell Cycle; Cell Nucleolus; History, 20th Century; History, 21st Century; RNA, Messenger; RNA, Ribosomal; Signal Recognition Particle; Virus Replication
PubMed: 21106648
DOI: 10.1101/cshperspect.a000638 -
Cells Jun 2019The nucleolus is the largest substructure in the nucleus, where ribosome biogenesis takes place, and forms around the nucleolar organizer regions (NORs) that comprise... (Review)
Review
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.
Topics: Animals; Cell Nucleolus; Embryonic Stem Cells; Genome; Genomic Instability; Humans; RNA, Ribosomal
PubMed: 31212844
DOI: 10.3390/cells8060579 -
Genes Dec 2019Both the pericentromere and the nucleolus have unique characteristics that distinguish them amongst the rest of genome. Looping of pericentromeric DNA, due to structural... (Review)
Review
Both the pericentromere and the nucleolus have unique characteristics that distinguish them amongst the rest of genome. Looping of pericentromeric DNA, due to structural maintenance of chromosome (SMC) proteins condensin and cohesin, drives its ability to maintain tension during metaphase. Similar loops are formed via condensin and cohesin in nucleolar ribosomal DNA (rDNA). Condensin and cohesin are also concentrated in transfer RNA (tRNA) genes, genes which may be located within the pericentromere as well as tethered to the nucleolus. Replication fork stalling, as well as downstream consequences such as genomic recombination, are characteristic of both the pericentromere and rDNA. Furthermore, emerging evidence suggests that the pericentromere may function as a liquid-liquid phase separated domain, similar to the nucleolus. We therefore propose that the pericentromere and nucleolus, in part due to their enrichment of SMC proteins and others, contain similar domains that drive important cellular activities such as segregation, stability, and repair.
Topics: Adenosine Triphosphatases; Cell Cycle Proteins; Cell Nucleolus; Centromere; Chromosomal Proteins, Non-Histone; Chromosome Segregation; Chromosomes; DNA-Binding Proteins; Mitosis; Multiprotein Complexes; Nucleolus Organizer Region; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Cohesins
PubMed: 31835574
DOI: 10.3390/genes10121029 -
Molecular Cell Dec 2019Fibrillar centers (FCs) and dense fibrillar components (DFCs) are essential morphologically distinct sub-regions of mammalian cell nucleoli for rDNA transcription and...
Fibrillar centers (FCs) and dense fibrillar components (DFCs) are essential morphologically distinct sub-regions of mammalian cell nucleoli for rDNA transcription and pre-rRNA processing. Here, we report that a human nucleolus consists of several dozen FC/DFC units, each containing 2-3 transcriptionally active rDNAs at the FC/DFC border. Pre-rRNA processing factors, such as fibrillarin (FBL), form 18-24 clusters that further assemble into the DFC surrounding the FC. Mechanistically, the 5' end of nascent 47S pre-rRNA binds co-transcriptionally to the RNA-binding domain of FBL. FBL diffuses to the DFC, where local self-association via its glycine- and arginine-rich (GAR) domain forms phase-separated clusters to immobilize FBL-interacting pre-rRNA, thus promoting directional traffic of nascent pre-rRNA while facilitating pre-rRNA processing and DFC formation. These results unveil FC/DFC ultrastructures in nucleoli and suggest a conceptual framework for considering nascent RNA sorting using multivalent interactions of their binding proteins.
Topics: Active Transport, Cell Nucleus; Antigens, Nuclear; Cell Nucleolus; Chromosomal Proteins, Non-Histone; Female; HEK293 Cells; HeLa Cells; Humans; Nucleic Acid Conformation; Protein Binding; Protein Interaction Domains and Motifs; RNA Precursors; RNA Processing, Post-Transcriptional; RNA, Ribosomal
PubMed: 31540874
DOI: 10.1016/j.molcel.2019.08.014 -
Cells Sep 2022Besides the canonical function in ribosome biogenesis, there have been significant recent advances towards the fascinating roles of the nucleolus in stress response,... (Review)
Review
Besides the canonical function in ribosome biogenesis, there have been significant recent advances towards the fascinating roles of the nucleolus in stress response, cell destiny decision and disease progression. Nucleolar stress, an emerging concept describing aberrant nucleolar structure and function as a result of impaired rRNA synthesis and ribosome biogenesis under stress conditions, has been linked to a variety of signaling transductions, including but not limited to Mdm2-p53, NF-κB and HIF-1α pathways. Studies have uncovered that nucleolus is a stress sensor and signaling hub when cells encounter various stress conditions, such as nutrient deprivation, DNA damage and oxidative and thermal stress. Consequently, nucleolar stress plays a pivotal role in the determination of cell fate, such as apoptosis, senescence, autophagy and differentiation, in response to stress-induced damage. Nucleolar homeostasis has been involved in the pathogenesis of various chronic diseases, particularly tumorigenesis, neurodegenerative diseases and metabolic disorders. Mechanistic insights have revealed the indispensable role of nucleolus-initiated signaling in the progression of these diseases. Accordingly, the intervention of nucleolar stress may pave the path for developing novel therapies against these diseases. In this review, we systemically summarize recent findings linking the nucleolus to stress responses, signaling transduction and cell-fate decision, set the spotlight on the mechanisms by which nucleolar stress drives disease progression, and highlight the merit of the intervening nucleolus in disease treatment.
Topics: Cell Nucleolus; Disease Progression; Humans; NF-kappa B; Transcription, Genetic; Tumor Suppressor Protein p53
PubMed: 36230979
DOI: 10.3390/cells11193017 -
Neuroscience May 2023Tau is a well-known microtubule-associated protein related to its cytoplasmic localization in a neuronal cell. However, tau has been located at the cell nucleus where it... (Review)
Review
Tau is a well-known microtubule-associated protein related to its cytoplasmic localization in a neuronal cell. However, tau has been located at the cell nucleus where it could be a nucleic acid-associated protein by its preferential binding to DNA sequences present in the nucleolus and pericentromeric heterochromatin. This less well-known localization of tau could not be trivial, since during aging, an increase in the amount of nuclear tau takes place and it may be related to the described role of tau in the activation of transposons and further aging acceleration.
Topics: tau Proteins; Cell Nucleus; Cell Nucleolus; Cytosol
PubMed: 35872252
DOI: 10.1016/j.neuroscience.2022.07.015