Nucleus (Austin, Tex.)最新文献

In higher eukaryotes, the nucleolus harbors at least three sub-phases that facilitate multiple functionalities including ribosome biogenesis. The three prominent coexisting sub-phases are the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC). Here, we review recent efforts in profiling sub-phase compositions that shed light on the types of physicochemical properties that emerge from compositional biases and territorial organization of specific types of macromolecules. We highlight roles played by molecular grammars which refers to protein sequence features including the substrate binding domains, the sequence features of intrinsically disordered regions, and the multivalence of these distinct types of domains / regions. We introduce the concept of a barcode of emergent physicochemical properties of nucleoli. Although our knowledge of the full barcode remains incomplete, we hope that the concept prompts investigations into undiscovered emergent properties and engenders an appreciation for how and why unique microenvironments control biochemical reactions.

Abnormal cell nuclear shapes are hallmarks of diseases, including progeria, muscular dystrophy, and many cancers. Experiments have shown that disruption of heterochromatin and increases in euchromatin lead to nuclear deformations, such as blebs and ruptures. However, the physical mechanisms through which chromatin governs nuclear shape are poorly understood. To investigate how heterochromatin and euchromatin might govern nuclear morphology, we studied chromatin microphase separation in a composite coarse-grained polymer and elastic shell simulation model. By varying chromatin density, heterochromatin composition, and heterochromatin-lamina interactions, we show how the chromatin phase organization may perturb nuclear shape. Increasing chromatin density stabilizes the lamina against large fluctuations. However, increasing heterochromatin levels or heterochromatin-lamina interactions enhances nuclear shape fluctuations by a "wetting"-like interaction. In contrast, fluctuations are insensitive to heterochromatin's internal structure. Our simulations suggest that peripheral heterochromatin accumulation could perturb nuclear morphology, while nuclear shape stabilization likely occurs through mechanisms other than chromatin microphase organization.

Nucleoporins, essential proteins building the nuclear pore, are pivotal for ensuring nucleocytoplasmic transport. While traditionally confined to the nuclear envelope, emerging evidence indicates their presence in various cytoplasmic structures, suggesting potential non-transport-related roles. This review consolidates findings on cytoplasmic nucleoporin assemblies across different states, including normal physiological conditions, stress, and pathology, exploring their structural organization, formation dynamics, and functional implications. We summarize the current knowledge and the latest concepts on the regulation of nucleoporin homeostasis, aiming to enhance our understanding of their unexpected roles in physiological and pathological processes.

The eukaryotic translation initiation factor eIF4E acts as a multifunctional factor that simultaneously influences mRNA processing, export, and translation in many organisms. Its multifactorial effects are derived from its capacity to bind to the methyl-7-guanosine cap on the 5'end of mRNAs and thus can act as a cap chaperone for transcripts in the nucleus and cytoplasm. In this review, we describe the multifactorial roles of eIF4E in major mRNA-processing events including capping, splicing, cleavage and polyadenylation, nuclear export and translation. We discuss the evidence that eIF4E acts at two levels to generate widescale changes to processing, export and ultimately the protein produced. First, eIF4E alters the production of components of the mRNA processing machinery, supporting a widescale reprogramming of multiple mRNA processing events. In this way, eIF4E can modulate mRNA processing without physically interacting with target transcripts. Second, eIF4E also physically interacts with both capped mRNAs and components of the RNA processing or translation machineries. Further, specific mRNAs are sensitive to eIF4E only in particular mRNA processing events. This selectivity is governed by the presence of cis-acting elements within mRNAs known as USER codes that recruit relevant co-factors engaging the appropriate machinery. In all, we describe the molecular bases for eIF4E's multifactorial function and relevant regulatory pathways, discuss the basis for selectivity, present a compendium of ~80 eIF4E-interacting factors which play roles in these activities and provide an overview of the relevance of its functions to its oncogenic potential. Finally, we summarize early-stage clinical studies targeting eIF4E in cancer.

A 14-year boy is given a microscope by his parents. It is not a toy - but a real microscope. He deploys it to rediscover the biology he had known before, but now in a magnified world. With extraordinary intellectual gifts he then, and manifestly later becomes absorbed by the idea that all this, however mysterious at first glance, might be subject to rational understanding, with painstaking study. Thus, was the genesis of one of the greatest cell biologists of the 20^th century, Joseph Grafton Gall, who died 12 September 2024, at 96. He had been professionally active up until only a few years ago. There was no one like him in the modern era of cell biology and there will not be another figure like him anytime soon.

The analysis of nucleocytoplasmic transport of proteins and messenger RNA has been the focus of advanced microscopic approaches. Recently, it has been possible to identify and visualize individual pre-ribosomal particles on their way through the nuclear pore complex using both electron and light microscopy. In this review, we focused on the transport of pre-ribosomal particles in the nucleus on their way to and through the pores.

Cell division presents a challenge for eukaryotic cells: how can chromosomes effectively segregate within the confines of a membranous nuclear compartment? Different organisms have evolved diverse solutions by modulating the degree of nuclear compartmentalization, ranging from complete nuclear envelope breakdown to complete maintenance of nuclear compartmentalization via nuclear envelope expansion. Many intermediate forms exist between these extremes, suggesting that nuclear dynamics during cell division are surprisingly plastic. In this review, we highlight the evolutionary diversity of nuclear divisions, focusing on two defining characteristics: (1) chromosome compartmentalization and (2) nucleocytoplasmic transport. Further, we highlight recent evidence that nuclear behavior during division can vary within different cellular contexts in the same organism. The variation observed within and between organisms underscores the dynamic evolution of nuclear divisions tailored to specific contexts and cellular requirements. In-depth investigation of diverse nuclear divisions will enhance our understanding of the nucleus, both in physiological and pathological states.

Cell migration involves the actin cytoskeleton, and recently recognized nuclear involvement. In this study, we explore the impact of chromatin remodeling on cell migration using NIH 3T3 cells and a scratch wound assay subjected to pharmacological interventions. We inhibit histone deacetylases (HDACs) with Trichostatin A (TSA) and methyltransferase EZH2 with GSK126 to modulate chromatin compaction. Our results indicate that chromatin modifications impair wound closure efficiency, reduce individual cell migration speed, and disrupt migration persistence. Live-cell imaging reveals dynamic intranuclear chromatin remodeling and nuclear shape parameters during migration, influenced by both small- and large-scale chromatin remodeling. The altered nuclear shape is associated with disrupted cell and nuclear mechanics, suggesting a crucial interplay between chromatin remodeling, nuclear mechanics and migration. These findings shed light on the intricate connection between intranuclear chromatin dynamics, nuclear mechanics, and cell migration, providing a basis for further investigations into the molecular mechanisms governing these processes.

Cytogenetic bands reflect genomic organization in large blocks of DNA with similar properties. Because banding patterns are invariant, this organization may often be assumed unimportant for genome regulation. Results here challenge that view. Findings here suggest cytogenetic bands reflect a visible framework upon which regulated genome architecture is built. Given Alu and L1 densities differ in cytogenetic bands, we examined their distribution after X-chromosome inactivation or formation of senescent-associated heterochromatin foci (SAHFs). Alu-rich regions remain outside both SAHFs and the Barr Body (BB), affirming that the BB is not the whole chromosome but a condensed, L1-rich core. Hi-C analysis of senescent cells demonstrates large (~10 Mb) G-bands remodel as a contiguous unit, gaining distal intrachromosomal interactions as syntenic G-bands coalesce into SAHFs. Striking peaks of Alu within R-bands strongly resist condensation. Thus, large-scale segmental genome architectur relates to dark versus light cytogenetic bands and Alu-peaks, implicating both in chromatin regulation.