RESUMEN
The nucleolus is the largest membraneless organelle and nuclear body in mammalian cells. It is primarily 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 accounts for the most energy-consuming cellular process needed for cell growth, proliferation, and homeostasis. Despite the significance of this process, the substructural mechanistic principles of the nucleolar function in preribosome biogenesis have only recently begun to emerge. Here, we provide a new perspective using advanced super-resolution microscopy and single-molecule MINFLUX nanoscopy on the mechanistic principles governing ribosomal RNA-seeded nucleolar formation and the resulting tripartite suborganization of the nucleolus driven, in part, by liquid-liquid phase separation. With recent advances in the cryogenic electron microscopy (cryoEM) structural analysis of ribosome biogenesis intermediates, we highlight the current understanding of the step-wise assembly of preribosomal subunits in the nucleolus. Finally, we address how novel anticancer drug candidates target early steps in ribosome biogenesis to exploit these essential dependencies for growth arrest and tumor control.
Asunto(s)
Nucléolo Celular , Animales , Humanos , Nucléolo Celular/metabolismo , Nucléolo Celular/química , Microscopía , Ribosomas/metabolismo , Ribosomas/químicaRESUMEN
Biomolecular condensates appear throughout the cell, serving many different biochemical functions. We argue that condensate functionality is optimized when the interactions driving condensation vary widely in affinity. Strong interactions provide structural specificity needed to encode functional properties but carry the risk of kinetic arrest, while weak interactions allow the system to remain dynamic but do not restrict the conformational ensemble enough to sustain specific functional features. To support our opinion, we describe illustrative examples of the interplay of strong and weak interactions that are found in the nucleolus, SPOP/DAXX condensates, polySUMO/polySIM condensates, chromatin, and stress granules. The common feature of these systems is a hierarchical assembly motif in which weak, transient interactions condense structurally defined functional units.
Asunto(s)
Garrapatas , Animales , Cromatina , Cinética , OrgánulosRESUMEN
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.
Asunto(s)
Envejecimiento/metabolismo , Nucléolo Celular/metabolismo , ADN Ribosómico/metabolismo , Células Eucariotas/metabolismo , Neoplasias/metabolismo , Ribosomas/metabolismo , Envejecimiento/genética , Ciclo Celular , Línea Celular Tumoral , Nucléolo Celular/genética , ADN Ribosómico/genética , Células Eucariotas/citología , Células Eucariotas/patología , Humanos , Mutación , Neoplasias/genética , Biosíntesis de Proteínas , Ribosomas/genéticaRESUMEN
Nuclear architecture plays a significant role in DNA repair mechanisms. It is evident that proteins involved in DNA repair are compartmentalized in not only spontaneously occurring DNA lesions or ionizing radiation-induced foci (IRIF), but a specific clustering of these proteins can also be observed within the whole cell nucleus. For example, 53BP1-positive and BRCA1-positive DNA repair foci decorate chromocenters and can appear close to nuclear speckles. Both 53BP1 and BRCA1 are well-described factors that play an essential role in double-strand break (DSB) repair. These proteins are members of two protein complexes: 53BP1-RIF1-PTIP and BRCA1-CtIP, which make a "decision" determining whether canonical nonhomologous end joining (NHEJ) or homology-directed repair (HDR) is activated. It is generally accepted that 53BP1 mediates the NHEJ mechanism, while HDR is activated via a BRCA1-dependent signaling pathway. Interestingly, the 53BP1 protein appears relatively quickly at DSB sites, while BRCA1 is functional at later stages of DNA repair, as soon as the Mre11-Rad50-Nbs1 complex is recruited to the DNA lesions. A function of the 53BP1 protein is also linked to a specific histone signature, including phosphorylation of histone H2AX (γH2AX) or methylation of histone H4 at the lysine 20 position (H4K20me); therefore, we also discuss an epigenetic landscape of 53BP1-positive DNA lesions.
Asunto(s)
Núcleo Celular/metabolismo , Reparación del ADN , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Núcleo Celular/genética , Humanos , Fosforilación , Proteína 1 de Unión al Supresor Tumoral P53/genéticaRESUMEN
Proteins and RNAs inside the cell nucleus are organized into distinct phases, also known as liquid-liquid phase separated (LLPS) droplet organelles or nuclear bodies. These regions exist within the spaces between chromatin-rich regions but their function is tightly linked to gene activity. They include major microscopically-observable structures such as the nucleolus, paraspeckle and Cajal body. The biochemical and assembly factors enriched inside these microenvironments regulate chromatin structure, transcription, and RNA processing, and other important cellular functions. Here, we describe published evidence that suggests nuclear bodies are bona fide LLPS droplet organelles and major regulators of the processes listed above. We also outline an updated "Supply or Sequester" model to describe nuclear body function, in which proteins or RNAs are supplied to surrounding genomic regions or sequestered away from their sites of activity. Finally, we describe recent evidence that suggests these microenvironments are both reflective and drivers of diverse pathophysiological states.
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Estructuras del Núcleo Celular/metabolismo , Núcleo Celular/química , Separación Celular , Epigénesis Genética/genética , Extracción Líquido-Líquido , Orgánulos/metabolismo , ARN/metabolismo , Núcleo Celular/metabolismo , Estructuras del Núcleo Celular/química , Estructuras del Núcleo Celular/genética , Humanos , Orgánulos/química , Orgánulos/genética , Tamaño de la Partícula , ARN/genética , ARN/aislamiento & purificaciónRESUMEN
Cells are segregated into two distinct compartment groups to optimize cellular function. The first is characterized by lipid membranes that encapsulate specific regions and regulate macromolecular flux. The second, known collectively as membraneless organelles (MLOs), lacks defining lipid membranes and exhibits self-organizing properties. MLOs are enriched with specific RNAs and proteins that catalyze essential cellular processes. A prominent sub-class of MLOs are known as nuclear bodies, which includes nucleoli, paraspeckles, and other droplets. These microenvironments contain specific RNAs, exhibit archetypal liquid-liquid phase separation characteristics, and harbor intrinsically disordered, multivalent hub proteins. We present an analysis of nuclear body protein disorder that suggests MLO proteomes are significantly more disordered than structured cellular features. We also outline common MLO ultrastructural features, exemplified by the three sub-compartments present inside the nucleolus. A core-shell configuration, or phase within a phase, is displayed by several nuclear bodies and may be functionally important. Finally, we summarize evidence indicating extensive RNA and protein sharing between distinct nuclear bodies, suggesting functional cooperation and similar nucleation principles. Considering the substantial accumulation of specific coding and noncoding RNA classes inside MLOs, evidence that RNA buffers specific phase transition events, and the absence of a clear correlation between total intrinsic protein disorder and MLO accumulation, we conclude that RNA biogenesis may play a key role in MLO formation, internal organization, and function. This article is categorized under: RNA Export and Localization > RNA Localization RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
Asunto(s)
Núcleo Celular/metabolismo , Orgánulos/metabolismo , Animales , Núcleo Celular/química , Humanos , Orgánulos/química , Proteoma/metabolismo , ARN/metabolismoRESUMEN
Integrator (INT) is a transcriptional regulatory complex associated with RNA polymerase II that is required for the 3'-end processing of both UsnRNAs and enhancer RNAs. Integrator subunits 9 (INTS9) and INTS11 constitute the catalytic core of INT and are paralogues of the cleavage and polyadenylation specificity factors CPSF100 and CPSF73. While CPSF73/100 are known to associate with a third protein called Symplekin, there is no paralog of Symplekin within INT raising the question of how INTS9/11 associate with the other INT subunits. Here, we have identified that INTS4 is a specific and conserved interaction partner of INTS9/11 that does not interact with either subunit individually. Although INTS4 has no significant homology with Symplekin, it possesses N-terminal HEAT repeats similar to Symplekin but also contains a ß-sheet rich C-terminal region, both of which are important to bind INTS9/11. We assess three functions of INT including UsnRNA 3'-end processing, maintenance of Cajal body structural integrity, and formation of histone locus bodies to conclude that INTS4/9/11 are the most critical of the INT subunits for UsnRNA biogenesis. Altogether, these results indicate that INTS4/9/11 compose a heterotrimeric complex that likely represents the Integrator 'cleavage module' responsible for its endonucleolytic activity.
Asunto(s)
Endorribonucleasas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Drosophila/metabolismo , Células HeLa , Humanos , Proteínas Nucleares/química , ARN Nuclear Pequeño/metabolismo , Técnicas del Sistema de Dos HíbridosRESUMEN
An intrinsic and essential trait exhibited by cells is the properly coordinated and integrated regulation of an astoundingly large number of simultaneous molecular decisions and reactions to maintain biochemical homeostasis. This is especially true inside the cell nucleus, where the recognition of DNA and RNA by a vast range of nucleic acid-interacting proteins organizes gene expression patterns. However, this dynamic system is not regulated by simple "on" or "off" signals. Instead, transcription factor and RNA polymerase recruitment to DNA are influenced by the local chromatin and epigenetic environment, a gene's relative position within the nucleus and the action of noncoding RNAs. In addition, major phase-separated structural features of the nucleus, such as nucleoli and paraspeckles, assemble in direct response to specific transcriptional activities and, in turn, influence global genomic function. Currently, the interpretation of these data is trapped in a causality dilemma reminiscent of the "chicken and the egg" paradox as it is unclear whether changes in nuclear architecture promote RNA function or vice versa. Here, we review recent advances that suggest a complex and interdependent interaction network between gene expression, chromatin topology, and noncoding RNA function. We also discuss the functional links between these essential nuclear processes from the nanoscale (gene looping) to the macroscale (sub-nuclear gene positioning and nuclear body function) and briefly highlight some of the challenges that researchers may encounter when studying these phenomena.
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Núcleo Celular/metabolismo , Cromatina/metabolismo , Regulación de la Expresión Génica , ARN Largo no Codificante/metabolismo , Animales , ADN/metabolismo , Epigénesis Genética , Humanos , Análisis EspacialRESUMEN
The assembly of specialized sub-nuclear microenvironments known as nuclear bodies (NBs) is important for promoting efficient nuclear function. In particular, the Cajal body (CB), a prominent NB that facilitates spliceosomal snRNP biogenesis, assembles in response to genomic cues. Here, we detail the factors that regulate CB assembly and structural maintenance. These include the importance of transcription at nucleating gene loci, the grouping of these genes on human chromosomes 1, 6 and 17, as well as cell cycle and biochemical regulation of CB protein function. We also speculate on the correlation between CB formation and RNA splicing levels in neurons and cancer. The timing and location of these specific molecular events is critical to CB assembly and its contribution to genome function. However, further work is required to explore the emerging biophysical characteristics of CB assembly and the impact upon subsequent genome reorganization.
Asunto(s)
Cuerpos Enrollados/metabolismo , Genoma , Genómica , Animales , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Cuerpos Enrollados/genética , Genómica/métodos , Histonas/genética , Histonas/metabolismo , Humanos , Unión Proteica , Empalme del ARN , Ribonucleoproteínas Nucleares Pequeñas/metabolismo , Empalmosomas/metabolismo , Transcripción GenéticaRESUMEN
Nuclear bodies contribute to non-random organization of the human genome and nuclear function. Using a major prototypical nuclear body, the Cajal body, as an example, we suggest that these structures assemble at specific gene loci located across the genome as a result of high transcriptional activity. Subsequently, target genes are physically clustered in close proximity in Cajal body-containing cells. However, Cajal bodies are observed in only a limited number of human cell types, including neuronal and cancer cells. Ultimately, Cajal body depletion perturbs splicing kinetics by reducing target small nuclear RNA (snRNA) transcription and limiting the levels of spliceosomal snRNPs, including their modification and turnover following each round of RNA splicing. As such, Cajal bodies are capable of shaping the chromatin interaction landscape and the transcriptome by influencing spliceosome kinetics. Future studies should concentrate on characterizing the direct influence of Cajal bodies upon snRNA gene transcriptional dynamics. Also see the video abstract here.
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Cuerpos Enrollados/genética , Genoma Humano , Empalmosomas , Transcriptoma , Cuerpos Enrollados/metabolismo , HumanosRESUMEN
The classic archetypal function of nuclear bodies is to accelerate specific reactions within their crowded space. In this issue, Tatomer et al. (2016. J. Cell Biol http://dx.doi.org/10.1083/jcb.201504043) provide the first direct evidence that the histone locus body acts to concentrate key factors required for the proper processing of histone pre-mRNAs.
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Cuerpos de Inclusión Intranucleares/metabolismo , Animales , Drosophila melanogaster/metabolismo , Histonas/metabolismo , Humanos , Modelos Biológicos , ARN/metabolismo , Ribonucleoproteína Nuclear Pequeña U7/metabolismoRESUMEN
A concern in the field of genomics is the proper interpretation of large, high-throughput sequencing datasets. The use of DNA FISH followed by high-content microscopy is a valuable tool for validation and contextualization of frequently occurring gene pairing events at the single-cell level identified by deep sequencing. However, these techniques possess certain limitations. Firstly, they do not permit the study of colocalization of many gene loci simultaneously. Secondly, the direct assessment of the relative position of many clustered gene loci within their respective chromosome territories is impossible. Thus, methods are required to advance the study of higher-order nuclear and cellular organization. Here, we describe a multiplexed DNA FISH technique combined with indirect immunofluorescence to study the relative position of 6 distinct genomic or cellular structures. This can be achieved in a single hybridization step using spectral imaging during image acquisition and linear unmixing. Here, we detail the use of this method to quantify gene pairing between highly expressed spliceosomal genes and compare these data to randomly positioned in silico simulated gene clusters. This is a potentially universally applicable approach for the validation of 3C-based technologies, deep imaging of spatial organization within the nucleus and global cellular organization.
Asunto(s)
Genómica/métodos , Hibridación Fluorescente in Situ/métodos , ADN/genética , Técnica del Anticuerpo Fluorescente , Células HeLa , Humanos , MicroscopíaRESUMEN
The mechanisms underlying nuclear body (NB) formation and their contribution to genome function are unknown. Here we examined the non-random positioning of Cajal bodies (CBs), major NBs involved in spliceosomal snRNP assembly and their role in genome organization. CBs are predominantly located at the periphery of chromosome territories at a multi-chromosome interface. Genome-wide chromosome conformation capture analysis (4C-seq) using CB-interacting loci revealed that CB-associated regions are enriched with highly expressed histone genes and U small nuclear or nucleolar RNA (sn/snoRNA) loci that form intra- and inter-chromosomal clusters. In particular, we observed a number of CB-dependent gene-positioning events on chromosome 1. RNAi-mediated disassembly of CBs disrupts the CB-targeting gene clusters and suppresses the expression of U sn/snoRNA and histone genes. This loss of spliceosomal snRNP production results in increased splicing noise, even in CB-distal regions. Therefore, we conclude that CBs contribute to genome organization with global effects on gene expression and RNA splicing fidelity.
Asunto(s)
Cuerpos Enrollados/genética , Genoma Humano , Conformación de Ácido Nucleico , Cromosomas Humanos/genética , Epigénesis Genética , Sitios Genéticos , Células HeLa , Histonas/genética , Humanos , Hibridación Fluorescente in Situ , ARN Polimerasa II/química , ARN Polimerasa II/metabolismo , Empalme del ARN/genética , ARN Nuclear Pequeño/genética , ARN Nucleolar Pequeño/genética , Reproducibilidad de los Resultados , Eliminación de Secuencia , Empalmosomas/metabolismo , Transcripción GenéticaRESUMEN
Mesenchymal stem cells' differentiation into several lineages is coordinated by a complex of transcription factors and co-regulators which bind to specific gene promoters. The Chromatin-Related Mesenchymal Modulator, CHD9 demonstrated in vitro its ability for remodeling activity to reposition nucleosomes in an ATP-dependent manner. Epigenetically, CHD9 binds with modified H3-(K9me2/3 and K27me3). Previously, we presented a role for CHD9 with RNA Polymerase II (Pol II)-dependent transcription of tissue specific genes. Far less is known about CHD9 function in RNA Polymerase I (Pol I) related transcription of the ribosomal locus that also drives specific cell fate. We here describe a new form, the nucleolar CHD9 (n-CHD9) that is dynamically associated with Pol I, fibrillarin, and upstream binding factor (UBF) in the nucleoli, as shown by imaging and molecular approaches. Inhibitors of transcription disorganized the nucleolar compartment of transcription sites where rDNA is actively transcribed. Collectively, these findings link n-CHD9 with RNA pol I transcription in fibrillar centers. Using chromatin immunoprecipitation (ChIP) and tilling arrays (ChIP- chip), we find an association of n-CHD9 with Pol I related to rRNA biogenesis. Our new findings support the role for CHD9 in chromatin regulation and association with rDNA genes, in addition to its already known function in transcription control of tissue specific genes.
Asunto(s)
Diferenciación Celular/genética , ADN Ribosómico/genética , Células Madre Mesenquimatosas/citología , Transactivadores/genética , Animales , Células COS , Linaje de la Célula , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Chlorocebus aethiops , Cromatina/genética , ADN Helicasas , Regulación de la Expresión Génica , Genes de ARNr , Células Madre Mesenquimatosas/metabolismo , Ratones , Proteínas del Complejo de Iniciación de Transcripción Pol1/genética , Proteínas del Complejo de Iniciación de Transcripción Pol1/metabolismo , ARN Polimerasa I/genética , ARN Polimerasa I/metabolismo , Ribosomas/genética , Transactivadores/metabolismoRESUMEN
The nucleus is a complex organelle containing numerous highly dynamic, structurally stable domains and bodies, harboring functions that have only begun to be defined. However, the molecular mechanisms for their formation are still poorly understood. Recently it has been shown that a nuclear body can form de novo by self-organization. But little is known regarding what triggers the formation of a nuclear body and how subsequent assembly steps are orchestrated. Nuclear bodies are frequently associated with specific active gene loci that directly contribute to their formation. Both coding and noncoding RNAs can initiate the assembly of nuclear bodies with which they are physiologically associated. Thus, the formation of nuclear bodies occurs via recruitment and consequent accumulation of resident proteins in the nuclear bodies by nucleating RNA acting as a seeder. In this chapter I describe how to set up an experimental cell system to probe de novo biogenesis of a nuclear body by nucleating RNA and nuclear body components tethered on chromatin.
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Núcleo Celular/genética , Núcleo Celular/metabolismo , Hibridación Fluorescente in Situ/métodos , Línea Celular Tumoral , Clonación Molecular/métodos , Cuerpos Enrollados/genética , Cuerpos Enrollados/metabolismo , Proteínas Fluorescentes Verdes/genética , Células HeLa , Histonas/genética , Humanos , Operón Lac/genética , Represoras Lac/genética , Proteínas Nucleares/genética , Transcripción GenéticaRESUMEN
UNLABELLED: The establishment of a latent reservoir by human tumor viruses is a vital step in initiating cellular transformation and represents a major shortcoming to current therapeutic strategies and the ability to eradicate virus-infected cells. Human T-cell leukemia virus type 1 (HTLV-1) establishes a lifelong infection and is linked to adult T-cell leukemia lymphoma (ATLL). Here, we demonstrate that HTLV-1 p30 recruits the cellular proteasome activator PA28γ onto the viral tax/rex mRNA to prevent its nuclear export and suppress virus replication. Interaction of p30 with a PA28γ retaining fully functional proteasome activity is required for p30's ability to repress HTLV-1. Consistently, HTLV-1 molecular clones replicate better and produce more virus particles in PA28γ-deficient cells. These results define a unique and novel role for the cellular factor PA28γ in the control of nuclear RNA trafficking and HTLV-1induced latency. Importantly, knockdown of PA28γ expression in ATLL cells latently infected with HTLV-1 reactivates expression of viral tax/rex RNA and the Tax protein. Because Tax is the most immunogenic viral antigen and triggers strong CTL responses, our results suggest that PA28γ-targeted therapy may reactivate virus expression from latently infected cells and allow their eradication from the host. KEY POINTS: PA28γ acts as a co-repressor of HTLV-1 p30 to suppress virus replication and is required for the maintenance of viral latency. HTLV-1 has evolved a unique function mediated by its posttranscriptional repressor p30, which is not found in HTLV-2.
Asunto(s)
Autoantígenos/metabolismo , Virus Linfotrópico T Tipo 1 Humano/fisiología , Complejo de la Endopetidasa Proteasomal/metabolismo , Latencia del Virus/fisiología , Replicación Viral/fisiología , Animales , Autoantígenos/genética , Transporte Biológico Activo/genética , Línea Celular , Regulación Viral de la Expresión Génica/fisiología , Productos del Gen rex/genética , Productos del Gen rex/metabolismo , Productos del Gen tax/genética , Productos del Gen tax/metabolismo , Humanos , Ratones , Ratones Noqueados , Complejo de la Endopetidasa Proteasomal/genética , ARN Viral/genética , ARN Viral/metabolismoRESUMEN
The mammalian cell nucleus is compartmentalized into nonmembranous subnuclear domains that regulate key nuclear functions. Nuclear speckles are subnuclear domains that contain pre-mRNA processing factors and noncoding RNAs. Many of the nuclear speckle constituents work in concert to coordinate multiple steps of gene expression, including transcription, pre-mRNA processing and mRNA transport. The mechanism that regulates the formation and maintenance of nuclear speckles in the interphase nucleus is poorly understood. In the present study, we provide evidence for the involvement of nuclear speckle resident proteins and RNA components in the organization of nuclear speckles. SR-family splicing factors and their binding partner, long noncoding metastasis-associated lung adenocarcinoma transcript 1 RNA, can nucleate the assembly of nuclear speckles in the interphase nucleus. Depletion of SRSF1 in human cells compromises the association of splicing factors to nuclear speckles and influences the levels and activity of other SR proteins. Furthermore, on a stably integrated reporter gene locus, we demonstrate the role of SRSF1 in RNA polymerase II-mediated transcription. Our results suggest that SR proteins mediate the assembly of nuclear speckles and regulate gene expression by influencing both transcriptional and posttranscriptional activities within the cell nucleus.
Asunto(s)
Núcleo Celular/metabolismo , Proteínas Nucleares/metabolismo , Precursores del ARN/metabolismo , Empalme del ARN , Proteínas de Unión al ARN/metabolismo , Animales , Línea Celular Tumoral , Núcleo Celular/genética , Células Cultivadas , Células HeLa , Humanos , Immunoblotting , Hibridación Fluorescente in Situ , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Noqueados , Microscopía Confocal , Microscopía Fluorescente , Proteínas Nucleares/genética , Unión Proteica , Interferencia de ARN , ARN Polimerasa II/metabolismo , Precursores del ARN/genética , ARN no Traducido/genética , ARN no Traducido/metabolismo , Proteínas de Unión al ARN/genética , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Factores de Empalme Serina-Arginina , Transcripción GenéticaRESUMEN
Despite past progress in understanding mechanisms of cellular mechanotransduction, it is unclear whether a local surface force can directly alter nuclear functions without intermediate biochemical cascades. Here we show that a local dynamic force via integrins results in direct displacements of coilin and SMN proteins in Cajal bodies and direct dissociation of coilin-SMN associated complexes. Spontaneous movements of coilin increase more than those of SMN in the same Cajal body after dynamic force application. Fluorescence resonance energy transfer changes of coilin-SMN depend on force magnitude, an intact F-actin, cytoskeletal tension, Lamin A/C, or substrate rigidity. Other protein pairs in Cajal bodies exhibit different magnitudes of fluorescence resonance energy transfer. Dynamic cyclic force induces tiny phase lags between various protein pairs in Cajal bodies, suggesting viscoelastic interactions between them. These findings demonstrate that dynamic force-induced direct structural changes of protein complexes in Cajal bodies may represent a unique mechanism of mechanotransduction that impacts on nuclear functions involved in gene expression.
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Cuerpos Enrollados/metabolismo , Lamina Tipo A/metabolismo , Actinas/genética , Actinas/metabolismo , Animales , Transferencia Resonante de Energía de Fluorescencia , Células HeLa , Humanos , Lamina Tipo A/genética , Ratones , Ratones Noqueados , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Plectina/genética , Plectina/metabolismoRESUMEN
It has become increasingly apparent that gene expression is regulated by the functional interplay between spatial genome organization and nuclear architecture. Within the nuclear environment a variety of distinct nuclear bodies exist. They are dynamic, self-organizing structures that do not assemble as pre-formed entities but rather emerge as a direct reflection of specific activities associated with gene expression and genome maintenance. Here I summarize recent findings on functions of some of the most prominent nuclear bodies, including the nucleolus, Cajal body, PML nuclear body, Polycomb group body and the 53BP1 nuclear body. The emerging view is that their organization is orchestrated by similar principles, and they function in fundamental cellular processes involved in homeostasis, differentiation, development and disease.