# Mechanobiology of the nucleolus

Yuthika Shetty, Monika Elzbieta Dolega

► To cite this version:

Yuthika Shetty, Monika Elzbieta Dolega. Mechanobiology of the nucleolus. 2025. hal-05311834

HAL Id: hal-05311834

https://hal.science/hal-05311834v1

Preprint submitted on 13 Oct 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# 1 Mechanobiology of the nucleolus

## 2 Yuthika Shetty and Monika Elzbieta Dolega*

## 3 Institute for Advanced Biosciences, University of Grenoble-Alpes, CNRS UMR5309, INSERM U1209; La

## 4 Tronche, 38700, France

## 5 * Correspondence: [monika.dolega@univ-grenoble-alpes.fr](mailto:monika.dolega@univ-grenoble-alpes.fr)

## 6 Abstract

Ribosome biogenesis is an essential and energy-demanding process required to maintain cellular proteostasis. The nucleolus, which orchestrates this vital process, assembles as a nuclear condensate and exhibits remarkable plasticity in its structure, function, and protein composition. Owing to its membraneless nature, the nucleolus participates in diverse signaling pathways, influencing cell cycle regulation, proliferation, apoptosis, differentiation and cellular stress response. Here, we focus on how mechanical cues influence nucleolar biology. While classical mechanotransduction is mediated by membrane-anchored signaling proteins and the cytoskeleton that propagate forces within the cell, how these mechanisms extend to dynamically assembled, membraneless condensates remains unclear. In this review, we explore how mechanical stimuli impact the nucleolus, the most prominent nuclear condensate. We examine how extrinsic forces alter nuclear structure, consequently affecting nucleolar organization, and function. We highlight emerging evidence that positions the nucleolus as a potential effector of nuclear mechano-adaptation, linking extracellular matrix (ECM) cues, migration, confinement, and external mechanical stress to nucleolar assembly and ribosome production.

20
## 21 Introduction

Early dominant theories emphasized biochemical regulation as the primary pathway of regulating cell and tissue behavior. The fundamental shift in perspective came with early works by Wolff, Fell and Canti, who provided foundational empirical evidence of the impact of mechanical stimuli on tissue morphogenesis and development (1,2). Modern mechanobiology emerged in the late 20th century with the emergence of atomic force microscopy (AFM), optical tweezers and advanced imaging modalities.

These technologies enabled controlled perturbation of cell and tissue mechanical environment coupled with high-throughput imaging, providing comprehensive approaches to decode cellular biomechanics and the role of mechanical cues in cell functioning and tissue development.

Building on these historical foundations, mechanobiology now aims to decipher the intricate mechanisms through which cells sense, respond and adapt to their mechanical environment. Studies on cell-ECM interactions have uncovered a complex network of feedback mechanisms, wherein cells and the ECM are able to dynamically sense and modulate each other's mechanical properties to maintain tissue homeostasis (3–5). Moreover, changes in cell density, ECM availability, and matrix stiffness impose mechanical constraints on the cells, triggering downstream signaling responses (6,7).

The conversion of these extrinsic mechanical cues into intracellular biochemical signals, via membrane receptors and cytoskeletal elements, delineates the classical pathways of mechanotransduction. These pathways play a critical role in regulating cell fate and function, influencing major cellular events such as cell adhesion, migration, differentiation and proliferation (8,9). Conversely, dysregulation of the tissue mechanical environment has been linked to development of tissue dysplasia and fibrosis, processes that contribute to the progression of disease pathology in cancer and cardiovascular diseases (10–12). Thus, a deeper understanding of physiological mechanotransduction pathways is critical to understand disease progression and identify potential therapeutic targets.

At the cellular level, mechanotransduction begins at the cell surface, where integrins and cadherins couple the ECM and neighboring cells to the cytoskeleton and nuclear envelope (13) (Figure 1).
Mechanosensitive receptors such as Piezo and TRPV channels, and GPCRs undergo conformational changes under force, activating downstream signaling cascades (14,15). Forces are relayed via the cytoskeleton and through the LINC complex to the lamina and chromatin, altering nuclear mechanics (16,17). Cytoskeletal mechanosensing also drives transcriptional co-activators such as YAP/TAZ to enter the nucleus and reprogram gene expression (18). Together, these pathways illustrate how cells convert external forces into nuclear responses.

Alterations in nuclear architecture inevitably permeate across subnuclear domains — including the nucleolus, the most prominent nuclear condensate. Nucleolus serves as the site of ribosomal DNA (rDNA) transcription and ribosome biogenesis. The bulk of cellular RNA — dominated by rRNA — is produced in these membraneless assemblies of protein. Owing to the sheer volume of transcriptional activity, the nucleolus assembles as an active, phase separated condensate facilitating the assembly of pre-ribosomal subunits (19,20). This organelle exhibits a dynamic composition by maintaining constant molecular flux with the surrounding nucleoplasm, allowing rapid transcriptional repression and response to extracellular stressors (21–23). Due to its membraneless nature, however, the nucleolus largely bypasses classical mechanotransduction pathways which rely on membrane-associated mechanosensing.

While the influence of mechanics on the nucleus is well established, whether such paradigms extend to membraneless nuclear condensates like the nucleolus remains unclear. Beyond lamina and chromatin coupling of cytoskeletons, early bead-displacement assays demonstrated that cytoskeletal prestress and actin organization can directly influence nucleolar mobility, revealing a physical linkage between the cytoskeleton and nucleolus (24,25). By contrast, pharmacological perturbation of actin showed minimal changes in nucleolar morphology (26), underscoring that this connection may be context dependent. These findings raise important questions regarding both the mechanisms by which external forces propagate to membraneless assemblies like the nucleolus, and the downstream consequences of such mechanical coupling. In this review, we therefore highlight the emerging and
underexplored dimension of nucleolar mechanobiology in the context of the cellular mechanical
environment. We examine seminal studies that have uncovered mechanically induced regulation of
nucleolar structure and function. We highlight the role of ECM cues, cell migration, confinement and
extrinsic mechanical stress on nucleolar structure, and function; both ribosomal biogenesis and cell
signaling. Given the novelty of this concept, we also highlight evidence from osmotic shock studies,
which effectively alter nuclear mechanics and carry strong implications for the nucleolus. Notably,
since osmotic shock also mechanically perturbs the nucleus, it may provide inspiration for uncovering
the currently unknown molecular pathways underlying nucleolar mechanoadaptation.
<figure><img src="image_2.png" /><figcaption>**Figure 1. Cellular structures involved in mechanotransduction.** Simplified view of an epithelial cell showing multiple adhesion complexes that mediate the transmission of forces (tensile, compressive, and shear stress) between the cell and the surrounding ECM or neighboring cells. Interaction with the ECM is regulated by focal adhesion complexes based on the transmembrane protein integrin. At the cell-cell interface, adherens junctions are regulated by cadherin-based complexes. Mechanosensitive channels such as Piezo and TRPV contribute to the sensing of tension, curvature, and shear stress. At the nuclear level, the LINC complex (linker of nucleoskeleton and cytoskeleton) is activated in response to tensile or compressive stresses, leading to mechanotransduction at the nuclear pores, nuclear lamina, chromatin, and nucleoli.</figcaption></figure>

79

80

81

82

83

84

85

86

87

88
89 Nucleolar structure and ribosome biogenesis

90 The nucleolus is the most prominent membraneless assembly within the nucleus, classified as a
91 biomolecular condensate, where the initial steps of ribosomal biogenesis occur. In recent decades,
92 high-resolution imaging and in vitro reconstitution studies have uncovered the tripartite organization
93 of the mammalian nucleolus consisting of fibrillar center (FC), dense fibrillar component (DFC), and
94 granular component (GC), emerging from a multiphase demixing of biological macromolecules (22,27)
95 (Figure 2a). The FC-DFC substructures are structurally linked rDNA transcriptional centers which appear
96 to be interspersed within the GC matrix. The spatiotemporal organization of these subcompartments
97 facilitates the sequential stages of rRNA synthesis and maturation by segregating these processes into
98 distinct compartments (Figure 2b), thereby enhancing efficiency (19,28). Despite lacking a membrane,
99 the nucleolus thus assembles with remarkable structural and functional precision.

100 The biophysical stability of the nucleolar condensate is underscored by its capacity to be biochemically
101 isolated from tissue lysates, reinforcing its classification as a distinct nuclear organelle (29). In contrast,
102 a large body of evidence demonstrates that the assembly of the nucleolus is driven by liquid-liquid
103 phase separation (LLPS) following the nucleation of RNA polymerase I (Pol I) complex at the nucleolar
104 organizer regions (NORs) of acrocentric chromosomes (22). The local enrichment of rDNA transcription
105 and ATP-dependent processes promote high-valency protein-protein and protein-RNA interactions,
106 driving the multiphase separation of subnucleolar compartments (26,30). This molecular organization
107 depends strongly on proteins with intrinsically disordered regions (IDRs), such as fibrillarin (GAR
108 domains) and nucleophosmin (NPM1; acidic tracts), which form multivalent RNA-protein interaction
109 networks(20,31,32). In vitro, fibrillarin and NPM1 co-assemble into core-shell droplets, consistent
110 with their distribution in vivo (27). These findings support a model in which active rDNA transcription
111 and ATP-dependent processes nucleate and facilitate LLPS events at nucleolar organizer regions
112 (NORs).
Beyond this internal phase behavior, nucleolar structure is influenced by structural components of the nucleus, including perinucleolar chromatin and the nuclear lamina (33). Perinucleolar chromatin forms a heterochromatic rim, enriched in nucleolus-associated domains (NADs) (34,35) overlap with lamina-associated domains (LADs), creating a complex chromatin architecture interfacing the nucleolar periphery and the nuclear lamina (36). Disruption of lamin A/C or lamin B perturbs nucleolar architecture, resulting in nucleolar shape abnormalities, fragmentation and altered rRNA synthesis (37-39). Thus, nuclear lamina and higher-order chromatin architecture contribute as critical structural regulators of the nucleolus, also influencing its spatial positioning and functioning.

Importantly, chromatin reorganization accompanies altered nucleolar functioning under stress. For instance, Pol I inhibition pharmacologically with CX-5461, or heat shock stress remodel perinucleolar heterochromatin and redistribute chromatin modifiers such as polycomb repressive complexes (PRC) (40-42). Moreover, specific pathways of epigenetic regulation of rDNA transcription have been outlined under stress conditions, which further link the nucleolar remodeling to chromatin organization (21,43,44). Such studies emphasize a strong functional link between chromatin state and nucleolar activity. Because chromatin and lamina are major load-bearing components of the nucleus which undergo rapid remodeling under mechanistic perturbations, their coupling to the nucleolus provides a plausible route by which mechanical forces reshape nucleolar structure and function.
<figure><img src="image_3.png" /><figcaption>**Figure 2.** Nucleolar structure and its role in ribosome biogenesis. A) Schematic of a eukaryotic cell showing the subnuclear membraneless organelle – the nucleolus. Nucleolar internal organization comprises three major compartments: the fibrillar center (FC; green), the dense fibrillar component (DFC; blue), and the granular component (GC; violet). Each of the compartments has a well-defined function, which is described in B) according to the compartment-related color code. Directional flux and processing stages impact the rheology of the nucleolus, with entangled pre-rRNA in the core (large gyration radius; Rg) rendering the nucleolus elastic, while progressive processing stages make the nucleolus more viscoelastic, culminating in the assembly of cleaved pre-rRNA with ribosomal proteins in the GC, which is characterized by viscous-like rheology.</figcaption></figure>
141 A biophysical look at the stress responsive nucleolus

142 Current literature characterizes the nucleolus as a viscoelastic, phase-separated biomolecular
143 condensate whose architecture is shaped by active rDNA transcription and multivalent protein-RNA
144 interactions (22). Building on this framework, a recent study using micropipette aspiration further
145 resolved the differential interfacial tension and rheological properties of its sub compartments (45).
146 The DFC exhibits viscoelastic solid dynamics, whereas the granular component (GC) relaxes with
147 Newtonian fluid-like behavior. These rheological differences likely arise from distinct protein
148 distributions and RNA dynamics within each compartment. For example, the hallmark DFC protein
149 fibrillarin displays gel-like elastic properties in reconstitution assays, implicating it in the DFC's relative
150 rigidity and elastic response (27). Additionally, evidence suggests that transcription and processing of
151 rRNA may contribute to these differential nucleolar material properties. Nascent rRNA transcripts form
152 an entangled mesh that becomes progressively less cross-linked as processing advances, thereby
153 contributing to the compartment-specific rheology (46) Such observations highlight that nucleolar
154 mechanics are not passive properties but are actively sculpted by ongoing molecular processes.
155 Optogenetically induced nucleolar gelation leads to an accumulation of unprocessed rRNA transcripts,
156 indicating a tunable, reciprocal interplay between condensate material properties and rRNA
157 maturation (47). Together, these findings underscore the active, spatiotemporally regulated processes
158 that sculpt nucleolar mechanics and support efficient ribosome assembly.

159 This biophysical model gains further depth when the nucleolus is challenged by stress. Across diverse
160 stresses — heat shock, osmotic changes, DNA damage, or nutrient deprivation — the nucleolus
161 undergoes remodeling and redistribution of key proteins such as NPM1 (48). We surveyed proteomic
162 datasets from UniProtKB and PDB to identify 7 most abundant nucleolar proteins and highlighted those
163 implicated in stress response (Table 1). Such nucleolar remodeling events activate well-characterized
164 stress pathways that fall into two classes: i) p53-dependent, where proteins like RPL11, NPM1, or ARF
165 stabilize p53 to regulate arrest, senescence, or apoptosis; and ii) p53-independent, involving
166 downstream responses by transcription factors such as E2F-1, MYC, or NF-κB (21,49). These canonical
pathways establish the nucleolus as a stress sensor and signaling hub. However, whether mechanical
inputs engage similar signaling routes or trigger distinct nucleolar responses remains largely
unexplored.

The remarkable plasticity of the nucleolus is evidenced by the different characteristic morphological
states described during nucleolar stress. A classic example is the formation of nucleolar caps upon
Actinomycin D treatment, in which DNA transcription stalls and DFC components relocalize to the
periphery (50). Inhibition of rRNA processing, by contrast, results in a nucleolar necklace morphology,
a beaded arrangement of rRNA processing factors around the nucleolar rim (51). Additionally, RNA
polymerase II (pol II) inhibition causes unraveling of fibrillar centers and fragmentation of the granular
component (52). Disruption of proteostasis through proteasome inhibition or protein misfolding,
triggers the formation of nucleolar aggresomes and amyloid bodies respectively (53,54). These
structures are characterized by the selective exclusion of most nucleolar proteins, the sequestration
of specific proteins and RNAs, and dramatic alterations in intra-nucleolar phase dynamics. (55).
Together, these stress morphologies illustrate how the nucleolus reorganizes under biochemical
perturbations, yet the influence of direct mechanical inputs on shaping nucleolar morphology remains
a largely unexplored field.

Emerging evidences from studies on cellular size scaling and mechanobiology report nuclear
condensate assembly to be significantly influenced by nuclear rheology. Extrinsic mechanical forces
are directly transmitted to the nucleus, primarily through an integrated cytoskeletal network of actin
filaments, intermediate filaments, and microtubules. (56) (Figure 1). As a result, nucleolar organization
is intimately linked to nuclear architecture under mechanical perturbation, which is approximately 10-
fold stiffer than the surrounding cytoplasm and occupies a significant fraction of cell volume.
Consequently, lamina and chromatin together contribute significantly to the overall cell mechanics
(57). Nuclear lamins form a filamentous elastic network at the inner nuclear membrane, which resist
large-scale nuclear deformation, while the viscoelastic chromatin provides internal load-bearing
192 resistance. Perturbation of these components induces distinct alterations in the nucleolar morphology
193 (38,58,59). For example, Lamin B1 depletion disrupts the biphasic organization of nucleolar sub
194 compartments. Similarly, loss of the structural LINC component SUN1 at the nuclear envelope induces
195 nucleolar hypertrophy and reduction in rRNA synthesis (60). Additionally, mechanical perturbation
196 induces dynamic condensation and decondensation of chromatin state, thereby altering nuclear
197 microrheology and modulating force distribution to subnuclear structures, including the nucleolus
198 (59). In contrast, nuclear mechanics is also influenced by the behavior of nuclear condensates, which
199 preferentially localize in the mechanically compliant, “softer” euchromatic regions (61). Studies on
200 condensate maturation report that growing condensates can physically restructure and exclude
201 surrounding chromatin, thereby altering local nuclear architecture (62,63). Furthermore, literature
202 evidence highlights the role of RNA binding proteins in reorganizing chromatin strands via phase
203 separation dynamics, which can modulate transcription and influence cell fate decisions in processes
204 such as differentiation or stress adaptation (64). Together, these evidences establish that nuclear
205 condensates — and the nucleolus in particular — are not merely passive, biophysically separated
206 assemblies. Instead, they actively participate in shaping nuclear mechanics.

207 **Direct evidences of Mechano-regulation of nucleolus**

208 Nucleolar assembly is closely linked to nuclear architecture. Because the nucleus is large and
209 viscoelastic, it often acts as a rate-limiting organelle during deformations such as migration through
210 constricted environments. Nuclear mechanotransduction pathways, including LINC complex signaling
211 and YAP/TAZ nuclear translocation, coordinate these adaptive responses (18). By contrast, the
212 nucleoplasm is predominantly viscous and fluid-like, housing chromatin that provides internal
213 mechanical resistance. While the nucleolus itself has long been viewed mainly as a site of ribosome
214 biogenesis, recent studies show that extracellular mechanical cues can directly perturb its structure
215 and function. Here, we highlight seminal findings demonstrating how ECM-derived signals, such as
216

surface geometry, stiffness, and topology, and mechanically challenging cellular processes such as
migration, confinement, and mechanical stress, affect nucleolar structure, composition and function.

217

218

Extracellular matrix cues

219

ECM cues regulate cell architecture, ultimately affecting cell size scaling, cytoskeletal rigidity, and
nuclear architecture. Pundel et al. observed that these changes directly impact membraneless
nucleolar assembly within cells (65). Restricting cell adhesion to collagen islands of 20 µm diameter
micropatterns compared to 50 µm islands, resulted in reduced nuclear volume and nucleolar
coalescence into single enlarged structures (Figure 3; *substrate geometry*). This architectural change
was associated with decreased ribosomal regulatory gene expression, reduced rDNA transcription, and
overall reduction in protein synthesis. Nucleoskeletal components underwent significant
reorganization under adhesion restriction, with lamin A/C redistributing to the nuclear periphery and
enlarged peripheral H3K9me3 heterochromatin domains, consistent with enhanced chromatin
compaction. Particle Image Velocimetry suggested that reduced adhesion and nuclear size scaling,
were accompanied by increased rigidity of the viscoelastic chromatin network. Conversely,
pharmacologically-induced chromatin decondensation restored nucleolar number and ribosome
biogenesis on restrictive micropatterns, indicating that these mechanically induced changes in
nucleolar organization are reversible. Similarly, siRNA-mediated knockdown of nuclear envelope LINC
component SYNE2 (nesprin-2), decreased nuclear volume and reduced nucleolar number and function
irrespective of micropattern size. This indicates ECM-modulated cytoskeletal architecture influences
nucleolar organization through nucleo-cytoskeletal coupling. Comparable effects were observed by
restricting cell adhesion capacity on softer matrices, where nuclei exhibited smaller volumes and fewer
nucleoli. Together, these findings support a model in which ECM-regulated modulation of nuclear
volume contributes to the control of nucleolar number and functionality.

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

At the population level, Jaecker et al. (Figure 3; *substrate stiffness*) showed that ECM stiffness and
spatial organization similarly regulate nucleolar architecture (66). In cultured sheets of epithelial cells,

240
matrix-adherent “leader” cell population exhibits significantly larger nucleolar areas and higher nucleolar counts per cell than “follower” cells during 72h of culture. Both populations display further enhancement of these nucleolar phenotype on stiffer substrates at 72h, implicating ECM rigidity as a key driver of nucleolar response, potentially through its effects on cell mechanics and focal adhesion assembly. Moreover, leader cells displayed thicker actin and vimentin networks, underscoring coordinated cytoskeletal remodeling accompanying nucleolar responses. Transmission electron microscopy revealed an elevated number of fibrillar centers in both leader population and on stiff matrices, consistent with heightened nucleolar activity. This was accompanied by increased chromatin compaction and H3K27me3 levels, closely linking mechanotransductive chromatin dynamics and nucleolar remodeling. Notably, Ki-67 proliferation markers are increased in leader cells and increased across both cell types on stiff matrices, while pharmacological disruption of cell-cycle progression or chromatin compaction abolished ECM-driven nucleolar phenotypes. These reports highlight a complex interplay between ECM regulated cell-cycle progression and chromatin compaction underlying nucleolar organization and functioning. In contrast, premalignant MCF10A and malignant cell lines maintained elevated nucleolar size and number regardless of ECM stiffness, recapitulating cancer-associated nucleolar hypertrophy. Thus, ECM cues regulate nucleolar organization by modulating nuclear volume and chromatin compaction at the single-cell level (65), and by coordinating cytoskeletal remodeling and cell-cycle progression in collectives (66). Together, these findings establish adhesive and stiffness-dependent control of nucleolar function.

Beyond changes in nuclear volume and nucleolar architecture, intrinsic nuclear topology also contributes to nucleolar structure and ribosome biogenesis. Recent studies demonstrate nuclear envelope invaginations modulate nucleolar function and ribosome biogenesis. For example, Zhuang et al. in their preprint manuscript documented that nucleoli in epithelial cells maintain frequent contact with the nuclear envelope, and categorized these morphologies as flat, dent and tunnel interactions (67). Characteristic high-curvature tunnel invaginations maintain stable nucleolar contact throughout interphase, and exhibit a positive correlation with rDNA transcription levels.
To probe the role of these invaginations on nucleolar activity, (67) described experiments on cells cultured on nanopillar arrays of different radii to generate nuclear deformations of different curvatures (Figure 3; *substrate topology*). They reported that high curvature pillars (150 nm radius), generate nuclear tunnel contact with the nucleoli, accompanied by significant increase in ribosomal biogenesis. Moreover, mechanically induced tunnel invaginations selectively enhanced nucleolar activity within nucleoli in direct contact with the tunnels, while non-contacted nucleoli within the same nucleus exhibited reduced transcriptional activity. Conversely, breast cancer and progeria cells showed diminished rRNA synthesis on low curvature nanopillars, confirming that substrate curvature directly modulated nucleolar function. Expansion microscopy revealed tunnel-associated nucleoli were enriched with reorganized lamin B1, nuclear pore complexes and Exportin-1, facilitating the nuclear invagination phenotype and ribosomal subunit export respectively. Moreover, these regions further exhibited reduced surrounding heterochromatin, including decreased nucleolus-associated domains (NADs) and lamina-associated domains (LADs), indicating an open chromatin architecture that facilitates ribosomal biogenesis. These findings establish that substrate topology can modulate nucleolar function through stable nuclear envelope invaginations, which create spatially enriched environments to support ribosomal transport and assembly, thereby selectively enhancing nucleolar functionality at the resolution of single nucleolus.

Together, these studies establish the ECM as a key regulator of nucleolar structure and activity, acting through nuclear volume control, chromatin remodeling, and cytoskeletal coupling. By linking single-cell adhesion, substrate stiffness, and collective behavior to nucleolar organization, they highlight how tissue mechanics can directly tune ribosome biogenesis and stress adaptability.
<figure><img src="image_4.png" /><figcaption>**Figure 3: Extracellular matrix cues alter nucleolar assembly and function.** A) Cells grown on constricted micropattern show altered adhesion and morphology of nucleus. B) Confocal immunofluorescence images of HaCaT keratinocytes grown on micropatterned surfaces for 24 h, stained for nucleus (DAPI, blue) and nucleolin (green). Scale bars = 10 µm. C) Nucleolar fusion events in cells transfected with Nucleolin-GFP seeded on 20 µm islands. D) Correlation and R2 (Pearson's coefficient) for nuclear area and nucleoli number per cell combined from HKs cultured on micropatterns, PA gels, or with low or high calcium. E) Schematic describing spatial and mechanical cues for epithelial monolayers as leader-follower position and matrix stiffness, posing the question of whether mechanosensitive nucleoli regulate protein synthesis. F) Merged images of nucleolin (color scale representing pixel intensity) and F-actin (grayscale) in MCF10A cells after 72 h of culture on soft and stiff polyacrylamide gels (scale bar = 20 µm). Insets in these images show 3D Imaris renderings of representative nuclei (transparent), with nucleoli depicted in white (scale bar = 3 µm). G) Percentage of cells with total nucleolar area ≥30 µm² for each condition after 72 h of culture. H) Illustration of top and side views of a cells cultured on a nanopillar substrate. I) MCF-10A cells seeded on nanopillars with gradient radii from 400 nm to 150 nm. Cells were pulse-labeled with EU (red hot) for 1 hour and then</figcaption></figure>
304 immunostained with anti-LaminB1 antibody (cyan). Color bar: EU intensity from low to high. Scale bar:

305 5 µm. Figure A, B, C and D reproduced and adapted from Pundel, et al. (65). Figure E and F reproduced

306 and adapted from Jaecker et al. (66). Figure H and I reproduced and adapted from Zhang et al. (67).
307 Cell migration and confinement

308 Migrating cells frequently encounter constricted pores or dense interstitial spaces that impose
309 substantial nuclear deformation. In vitro models of confined migration reveal that nucleoli undergo
310 dynamic reorganization under these conditions (61) (Figure 4a). Severe nuclear deformation, observed
311 during confined cell migration through micropores, induces frequent nucleolar fission and fusion
312 events, consistent with the LLPS model of nucleolar organization (Figure 4b). Notably, fusion events
313 persist after the nucleus exits confinement, whereas nucleoli undergoing fission were observed to
314 subsequently coalesce following nuclear passage through the constriction. The nucleus of migrating
315 cells displays a polarized chromatin architecture with a leading end containing relatively homogenous
316 chromatin distribution, and a trailing end with heterotypic chromatin organization marked by H2B-
317 mGFP. This spatial chromatin heterogeneity not only creates a variable mechanical landscape, but also
318 promotes spontaneous condensation of phase separating proteins in the softer euchromatic regions,
319 irrespective of functional relevance. Optogenetic manipulations using blue light-induced synthetic
320 Corelet nuclear condensates, confirmed that such chromatin landscapes enhance condensate
321 nucleation in migrating nuclei, implicating chromatin distribution as a regulator of nuclear condensate
322 dynamics (61). Moreover, nucleolar condensates tend to lag toward the trailing edge, alongside an
323 increase in perinucleolar heterochromatin accumulation. This localization bias suggests a complex
324 mechanically induced interface between viscoelastic chromatin and nucleolar dynamics during
325 extreme mechanical deformation.

326 Nucleoskeletal F actin components significantly contribute to nucleolar organization, as demonstrated
327 by (68) in isolated *Xenopus laevis* germinal vesicles. The filamentous network of nuclear F-actin
328 physically anchors the nucleoli, while immunodepletion or pharmacological inhibition of actin-
329 polymerization causes multiple nucleoli to coalesce into a single central body. Furthermore,
330 mechanical confinement induced contact between nucleoli is followed by reorganization and fusion of
331 the GC and DFC, producing enlarged nucleoli (Figure 4c). Interestingly, these fusion events were not
instantaneous as expected of simple liquid droplets. Instead, nucleoli undergo multiple contact events followed by delayed, regulated coalescence, implying an entropic or kinetic barrier to fusion (Figure 4d). By contrast, in mammalian cells, chromatin is the nucleoskeletal matrix which substantially influences nucleolar dynamics. Experimental and theoretical studies demonstrate that the viscoelastic chromatin network promotes nucleation of phase-separated condensates, while impeding their coalescence by imposing a kinetic barrier to chromatin rearrangement (69,70). Optogenetic experiments further reveal that condensates actively exclude chromatin during droplet formation, highlighting a mechanically regulated interface that stabilizes the organization of nuclear condensates (71). These findings align with the recent characterization of a perinucleolar shell compartment, enriched in heterochromatin-associated proteins at the nucleolar periphery. Collectively, these data indicate that chromatin reorganization, mechanically influenced by cell migration and confinement, plays a central role in nucleolar assembly and dynamics.

During migration, localized translation of cytoskeletal mRNAs at the leading edge supports protrusion formation and motility (72). A similar mechanism was reported by Dermit et al. who demonstrated that in mesenchymal-like migrating cells on microporous substrates (Figure 4e), the RNA-binding protein LARP6 directs ribosomal protein (RP) mRNAs to cytoplasmic protrusions, creating hotspots of RP synthesis that feed ribosome assembly in the nucleus (Figure 4f) (73). The newly synthesized ribosomal proteins are subsequently transported to the nucleus for ribosomal assembly. This mechanism links EMT-associated migration to increased ribosome biogenesis and nucleolar hypertrophy, a phenotype often observed in metastatic cancer.

Together, studies of migration and confinement reveal that mechanical deformation of the nucleus reshapes nucleolar architecture through fusion, fission, and chromatin remodeling. In parallel, localized translation of ribosomal proteins during migration couples cytoskeletal dynamics to nucleolar output. These findings position the nucleolus as a central integrator of mechanical stress and biosynthetic demand, with implications for both normal development and cancer invasion.
<figure><img src="image_5.png" /><figcaption>**Figure 4: Cell migration and nuclear confinement alter nucleolar dynamics and function**
A) Illustration of nucleoli in the nucleus undergoing mechanical deformation throughout the confined-migration event. B) Representative examples of NPM1-mCherry labeled nucleoli fusing during confined migration. Arrows: fusion events. Scale bar: 5 µm. C) Illustration of isolated germinal vesicles in oil confined to ~50% height under a coverslip. D) Timelapse images of bright-field and fluorescence microscopy showing regulated nucleolar fusion events. E) Illustration of transwell-based protrusion formation and the mechanism of LARP6 mediated translational hotspots. F) LARP6 co-localizes with RP-mRNAs in protrusions. Representative RNA-FISH and IF co-staining images of RPL34 mRNA (green) and LARP6 (red) in protrusions and cell bodies of MDA-MB231 cells. Cell boundaries (dashed lines) were defined from co-staining with anti-tubulin antibody. Figure A and B reproduced and adapted from Zhao et al.,</figcaption></figure>

357

358

359

360

361

362

363

364

365

366

367
368 (61). Figure C and D reproduced and adapted from Brangwynne et al. (68). Figure E and F reproduced

369 and adapted from Dermit et al. (73).
370 **Mechanical stress**

371 Beyond ribosome biogenesis, the nucleolus acts as a mechanosensitive hub, integrating physical stress
372 signals with cell fate decisions (21). While limited studies directly probe mechanotransduction at the
373 nucleolar level, some evidence exists that the nucleolus plays a crucial downstream signaling role in
374 regulating cell survival and fate. During cyclic mechanical stress (CMS), the autophagy marker LC3
375 undergoes translocation into nuclear and nucleolar compartments, accompanied by cellular
376 autophagy activation (74). Another mechanotransduction pathway based on focal adhesion kinase
377 (FAK) re-localization to the nucleolus is activated in breast carcinoma cells (75). FAK inhibition results
378 in depletion of the nucleolar protein nucleostemin (NS), while other nucleolar proteins such as
379 B23/NPM and nucleolin remain unchanged. In the nucleolus, FAK forms a signaling complex comprising
380 mTOR, Akt, NS, and FAK, suggesting nucleolar role in coordinating tumor progression and metastasis.
381 Overall these works illustrate that nucleolus functions as a selective signaling hub for targets beyond
382 ribosomes in mechanically stressed conditions.

383 Nucleolar function is regulated at several levels, including rDNA transcription, processing, assembly
384 and ribosomal protein availability. Transcriptomic and qPCR analyses of statically compressed
385 epithelial monolayers reveal significant downregulation of focal adhesion- and ECM-related
386 transcripts, with concurrent upregulation of proteins involved in ribosome biogenesis (76). This
387 demonstrates that cellular mechanical state impacts ribosome biogenesis and nucleolar functionality.
388 In addition to their roles in ribosome biogenesis within the nucleolus, ribosomal proteins also exhibit
389 extra-nucleolar signaling functions. (77) report significant decrease in the levels of RPL35 in
390 chondrocytes under cyclic mechanical stress, while its overexpression protects the cells against
391 mechanically-induced senescence and osteoarthritis (OA) development. Conversely, siRNA-mediated
392 knockdown of RPL35 accelerates OA progression, highlighting a significant role of nucleolar proteins in
393 downstream cell fate signaling during mechanical stress responses. Thus, the nucleolus, while
394 incompletely understood in the context of mechanotransduction, demonstrates established links to
395 mechanically-induced signaling during stress response.
396 **Physiological and pathological contexts of nucleolar mechanobiology**

397 Beyond experimental perturbations, nucleolar mechanobiology also manifests in physiological
398 contexts such as development and tissue growth, as well as in pathological states like cancer, where
399 altered mechanics reshape nucleolar structure and function. Interestingly, a study by Al Jord et al. (78)
400 demonstrated that cytoplasmic forces generated by F-actin and myosin motors are essential for
401 nucleolar reorganization during mouse oocyte growth and development. Similarly, skeletal muscle
402 hypertrophy drives coordinated growth of the nucleolus along with cell size in response to increased
403 protein-synthesis demands (79). These examples suggest that actomyosin activity and cellular growth
404 programs can directly tune nucleolar condensate size and organization.

405 In pathological contexts, many cancers exhibit nucleolar hypertrophy and elevated ribosome
406 biogenesis to support rapid proliferation (80). This phenotype may arise not only from oncogenic
407 transcriptional programs but also from aberrant mechanical cues in the tumor microenvironment,
408 which are known biophysical drivers of cancer progression. For instance, treatment of triple-negative
409 breast cancer cells with lovastatin induces actin depolymerization and G-actin relocalization to
410 nucleus, accompanied by nucleolar stress, decreased rRNA synthesis and loss of stem-like properties
411 (81). These findings underscore a potential therapeutic strategy where targeting cytoskeletal-
412 nucleolar coupling could reduce ribosome biogenesis and impair cancer cell adaptability.

413 Together, these examples illustrate physiological mechanoregulation of nucleolar condensate size and
414 dynamics within cells. In pathological contexts, they suggest that aberrant mechanical cues, likely
415 biophysical drivers of cancer pathology, concurrently influence nucleolar assembly. They strengthen
416 the view that the nucleolus acts as an integrator of both intracellular mechanics and external
417 microenvironmental cues, with implications for development, tissue plasticity, and disease.

418 Lessons from osmotic shock

419 Among non-classical stress paradigms, osmotic shock is relevant to mechanobiology studies because
420 it directly imposes mechanical load on the cell and nucleus. Changes in external osmolarity alter
421 nuclear pore permeability, nuclear envelope tension, and thereby protein concentration and dynamics
422 within the nucleus. Osmotic perturbations thus provide mechanistic and molecular insight into how
423 nucleolar condensates respond to mechanical and biochemical stress.

424 Hyperosmotic shock in yeast induces rapid nucleolar shrinkage and chromatin compaction, (82) while
425 hypoosmotic stress causes decondensation. Both are accompanied by nucleolar remodeling, including
426 dissociation of FC/DFC subcompartments and redistribution of key proteins such as nucleolin and
427 fibrillarin to the nucleoplasm (83,84). These effects are reversible upon restoration of osmotic balance,
428 highlighting nucleolar resilience but also its sensitivity to mechanical deformation. Notably,
429 PQBP5/NOL10 has been identified as an intrinsically disordered nucleolar scaffold protein which
430 remains associated with the nucleolus during osmotic stress (83). Depletion of NOL10 results in lack of
431 nucleolar assembly, while disruption of functional nucleolar proteins - nucleolin and fibrillarin - alters
432 nucleolar protein distribution without significantly affecting assembly. This highlights a subset of
433 nucleolar proteins contributing disproportionately to nucleolar structural resilience, and forming a
434 structural basis for nucleolar assembly.

435 Upon osmotic insults conserved stress-signaling pathways are activated. Rapid ion fluxes are followed
436 by osmolyte accumulation (85). In yeast, the stress-activated protein kinase (SAPK) Hog1, homolog of
437 the mammalian p38 mitogen-activated protein kinase (MAPK), orchestrates transcriptional and cell
438 cycle responses, while mammalian cells employ p38/JNK MAPKs to coordinate chromatin remodeling
439 and nucleolar surveillance (86,87). Osmotic stress can also induce formation of single-stranded R-loop
440 structures mediated by ATR/ATM activation via the nucleolar protein treacle, leading to transcriptional
441 silencing of ribosomal DNA (rDNA) (44). Together, osmotic perturbations highlight how nuclear
442 mechanics and stress signaling converge on the nucleolus to regulate its structure and function. (See
443 Table 1)
444 **Challenges and perspectives**

445 The primary challenge in studying the nucleolus lies in the absence of membrane boundaries, specific
446 receptor complexes, and fixed architecture. This membraneless nature means that the nucleolar
447 structure and composition is inherently dynamic and context-dependent. The absence of receptor-
448 mediated dynamics leaves an organelle primarily defined by local protein concentration and
449 distribution. Consequently, nucleolar behavior is simultaneously governed by active ATP-dependent
450 processes and material properties of the surrounding nucleoplasm (26). This requires a new paradigm
451 of looking at nucleolar mechanotransduction through the framework of intracellular phase transitions,
452 wherein mechanical forces modulate nuclear and chromatin architecture, intra-nuclear protein
453 composition and nucleolar function.

454 Progress in nucleolar mechanobiology depends on methodological advances. Current work often infers
455 nucleolar mechanics indirectly from nuclear/nucleolar deformation or chromatin state. More
456 quantitative biophysical tools are needed to directly measure nucleolar material properties under
457 mechanical perturbation. Live-cell imaging, optogenetics, and microfabricated environments will be
458 essential to probe nucleolar behavior in physiologically relevant mechanical contexts. In vivo studies
459 remain scarce, and their expansion will be critical to link nuclear mechanics and nucleolar organization
460 during development, tissue remodeling, and disease.

461 Finally, future perspectives highlight both fundamental and translational opportunities. Mechanically
462 induced nucleolar remodeling may contribute to physiological processes such as oocyte maturation
463 and muscle hypertrophy, but also to pathological states such as cancer, where nucleolar hypertrophy
464 supports uncontrolled proliferation. Targeting nucleolar function via cytoskeletal or nuclear mechanics
465 — as seen in recent work on actin depolymerization and rRNA suppression in breast cancer cells(26,81)
466 — may provide novel therapeutic strategies. Unraveling how external mechanical cues reshape
467 nucleolar condensates thus promises new insight into the integration of mechanics and cell biology,
468 with broad implications for health and disease.
<table><caption>**Table 1** Major nucleolar proteins and their role in stress response</caption><thead><tr><th>Protein</th><th>Functions</th><th>Sites of interaction</th><th>Protein mobility and type of stress</th><th>p53 dep.</th><th>Mechanism</th><th>Ref</th></tr></thead><tbody><tr><td>NPM1 (B23)</td><td>Ribosome biogenesis; histone chaperone; nucleocytoplasmic transport</td><td>N-terminal oligomerization domain; central acidic IDR; NLS; C-terminal nucleic-acid-binding domain</td><td>Translocates Out: oxidative stress, DNA damage, serum starvation, heat shock, osmotic stress</td><td>Yes</td><td>p53 stabilization; DNA repair; apoptosis regulation</td><td>(48)</td></tr><tr><td>HSPA8 (Hsc70)</td><td>Protein quality control; refolding; ubiquitination; protein translocation</td><td>N-terminal nucleotide-binding ATPase domain; central substrate-binding domain; C-terminal helical lid domain</td><td>Translocates In: heat shock, oxidative stress</td><td>No</td><td>ROS protection, Proteostasis</td><td>(88)</td></tr><tr><td>Nucleolin (C23)</td><td>rRNA transcription & maturation; nucleocytoplasmic transport; chromatin remodeling; cell cycle regulation</td><td>Basic N-terminal chromatin-binding domain; central RNA-binding domains; C-terminal GAR/RGG IDR</td><td>Translocates Out: heat shock, DNA damage, osmotic stress</td><td>Yes and No</td><td>p53-dependent replication inhibition; DNA damage repair, altered gene regulation</td><td>(83, 84)</td></tr><tr><td>RPL5 / RPL11</td><td>Ribosome biogenesis; 60S subunit components</td><td>RPL5: N-terminal globular domain (5S rRNA binding); C-terminal extension (RPL11 binding) RPL11: Conserved N-terminal domain of RNA binding proteins; C-terminal RNA binding homeodomain helix</td><td>Translocates Out: ribotoxic stress</td><td>Yes</td><td>p53 stabilization; cell cycle arrest</td><td>(89)</td></tr><tr><td>APE1</td><td>Base excision repair; rRNA quality control; gene regulation</td><td>Disordered N-terminal redox domain; C-terminal AP endonuclease domain</td><td>Translocates Out oxidative and genotoxic stress</td><td>Not given</td><td>rRNA oxidation and reduced protein translation. DNA damage response</td><td>(90, 91)</td></tr><tr><td>DDX5 (p68)</td><td>ATP-dependent RNA helicase; Gene-expression regulation</td><td>Two conserved domains (1 and 2) with nucleotide/ATP-binding sites and helicase activity; variable (IDR) N- and C-terminal sequences</td><td>Translocates In: p19ARF knockdown</td><td>No</td><td>Stimulates 47S transcription; increases ribosome output</td><td>(92)</td></tr><tr><td>FBL</td><td>pre-rRNA methylation; processing; pre-ribosome assembly</td><td>N-terminal GAR domain (IDR); central RNA-binding domain; C-terminal α-helical (methyltransferase) domain</td><td>Translocates Out: osmotic stress</td><td>Not known</td><td>Not Known</td><td>(83)</td></tr><tr><td>p14ARF</td><td>Tumor suppressor</td><td>N-terminal domain with hydrophobic clusters (MDM2-binding); C-terminal domain (nucleolar localization)</td><td>Translocates Out: heat shock, oxidative stress, Oncogenic stimuli</td><td>Yes and No</td><td>p53-dependent and independent cell cycle arrest and apoptosis</td><td>(93)</td></tr></tbody></table>
471 Acknowledgements

472 M.D is supported by the ANR funding agency (CellCOMM ANR-17-CE13-0006) and ARC funding

473 agency (NucleolarFORCE R24024CC RAC24005CCA).

474 Declaration of interests

475 The authors declare no competing interests.

476 Use of AI tools

477 ChatGPT (OpenAI, GPT-4) was used under author supervision to assist with language refinement and

478 to suggest potential literature during the drafting process. All references were independently verified,

479 selected, and cited by the authors. Chat-GPT assigned the list of proteins from UniProtKB with the

480 whole organism protein abundance data (PDB) to identify 7 most abundant nucleolar proteins that we

481 manually assigned their function in stress response. In the review, no AI-generated content, data, or

482 unverified citations were used. The authors take full responsibility for the accuracy and integrity of the

483 manuscript.
484 References

485 1. Fell HB, Canti RG. Experiments on the Development in vitro of the Avian Knee-Joint [Internet].
486 1934 [cited 2025 Sep 9]. Available from: https://www.jstor.org/stable/81873

487 2. Wolff J. Das gestetz der transformation der knochem. Verlag von August Hirschwald
488 [Internet]. 1892 [cited 2025 Sep 9]; Available from:
489 https://cir.nii.ac.jp/crid/1570854174931172096

490 3. Hall MS, Alisafaei F, Ban E, Feng X, Hui CY, Shenoy VB, et al. Fibrous nonlinear elasticity
491 enables positive Mechanical feedback between cells and ECMs. Proc Natl Acad Sci U S A
492 [Internet]. 2016 Dec 6 [cited 2025 Sep 9];113(49):14043-8. Available from:
493 https://www.pnas.org/doi/abs/10.1073/pnas.1613058113

494 4. Harris AK, Stopak D, Wild P. Fibroblast traction as a mechanism for collagen morphogenesis.
495 Nature 1981 290:5803 [Internet]. 1981 [cited 2025 Sep 9];290(5803):249-51. Available from:
496 https://www.nature.com/articles/290249a0

497 5. Winer JP, Oake S, Janmey PA. Non-Linear Elasticity of Extracellular Matrices Enables
498 Contractile Cells to Communicate Local Position and Orientation. PLoS One [Internet]. 2009 Jul
499 24 [cited 2025 Sep 9];4(7):e6382. Available from:
500 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006382

501 6. Natarajan V, Berglund EJ, Chen DX, Kidambi S. Substrate stiffness regulates primary
502 hepatocyte functions † HHS Public Access. RSC Adv. 2015;5(99):80956-66.

503 7. Zarkoob H, Bodduluri S, Ponnaluri S V., Selby JC, Sander EA. Substrate Stiffness Affects Human
504 Keratinocyte Colony Formation. Cell Mol Bioeng [Internet]. 2015 Mar 1 [cited 2025 Sep
505 9];8(1):32. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC4442095/

506 8. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage
507 specification. Cell [Internet]. 2006 Aug 25 [cited 2025 Sep 9];126(4):677-89. Available from:
508 https://pubmed.ncbi.nlm.nih.gov/16923388/

509 9. Ulrich TA, De Juan Pardo EM, Kumar S. The mechanical rigidity of the extracellular matrix
510 regulates the structure, motility, and proliferation of glioma cells. Cancer Res [Internet]. 2009
511 May 15 [cited 2025 Sep 9];69(10):4167. Available from:
512 https://pmc.ncbi.nlm.nih.gov/articles/PMC2727355/

513 10. Derrick CJ, Noel ES. The ECM as a driver of heart development and repair. Development
514 [Internet]. 2021 Mar 1 [cited 2025 Sep 13];148(5). Available from: https://pubmed-ncbi-nlm-
515 nih-gov.proxy.insermbiblio.inist.fr/33674261/

516 11. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. Matrix crosslinking forces tumor
517 progression by enhancing integrin signaling. Cell [Internet]. 2009 Nov 25 [cited 2025 Sep
518 9];139(5):891-906. Available from: https://pubmed.ncbi.nlm.nih.gov/19931152/

519 12. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional
520 homeostasis and the malignant phenotype. 2005;

521 13. Weber GF, Bjerke MA, DeSimone DW. Integrins and cadherins join forces to form adhesive
522 networks. J Cell Sci [Internet]. 2011 Apr 15 [cited 2025 Sep 9];124(8):1183. Available from:
523 https://pmc.ncbi.nlm.nih.gov/articles/PMC3115772/
524
525
526
527

14. Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, et al. Piezo1 and Piezo2 are essential components of distinct mechanically-activated cation channels. Science [Internet]. 2010 Oct 1 [cited 2025 Sep 9];330(6000):55. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC3062430/

528
529
530

15. Xu J, Mathur J, Vessières E, Hammack S, Nonomura K, Favre J, et al. GPR68 Senses Flow and Is Essential for Vascular Physiology. Cell [Internet]. 2018 Apr 19 [cited 2025 Sep 9];173(3):762-775.e16. Available from: https://www.cell.com/action/showFullText?pii=S0092867418304483

531
532
533

16. Carley E, Stewart RM, Zieman A, Jalilian I, King DE, Zubek A, et al. The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation. 2021 [cited 2025 Sep 13]; Available from: https://doi.org/10.7554/eLife.58541

534
535
536

17. Haase K, MacAdangdang JKL, Edrington CH, Cuerrier CM, Hadjiantoniou S, Harden JL, et al. Extracellular Forces Cause the Nucleus to Deform in a Highly Controlled Anisotropic Manner. Sci Rep. 2016 Feb 19;6.

537
538
539

18. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, et al. Role of YAP/TAZ in mechanotransduction. Nature 2011 474:7350 [Internet]. 2011 Jun 8 [cited 2025 Sep 9];474(7350):179-83. Available from: https://www.nature.com/articles/nature10137

540
541

19. Quinodoz SA, Jiang L, Abu-Alfa AA, Comi TJ, Zhao H, Yu Q, et al. Mapping and engineering RNA-driven architecture of the multiphase nucleolus. Nature. 2025 Aug 14;

542
543
544
545

20. Yao RW, Xu G, Wang Y, Shan L, Luan PF, Wang Y, et al. Nascent Pre-rRNA Sorting via Phase Separation Drives the Assembly of Dense Fibrillar Components in the Human Nucleolus. Mol Cell [Internet]. 2019 Dec 5 [cited 2025 Sep 13];76(5):767-783.e11. Available from: https://www.cell.com/action/showFullText?pii=S1097276519306306

546
547
548

21. Boulon S, Westman BJ, Hutten S, Boisvert FM, Lamond AI. The Nucleolus under Stress. Mol Cell [Internet]. 2010 Oct [cited 2025 Sep 13];40(2):216. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC2987465/

549
550
551
552

22. Lafontaine DLJ, Riback JA, Bascetin R, Brangwynne CP. The nucleolus as a multiphase liquid condensate. Nature Reviews Molecular Cell Biology 2020 22:3 [Internet]. 2020 Sep 1 [cited 2025 Sep 9];22(3):165-82. Available from: https://www.nature-com.proxy.insermbiblio.inist.fr/articles/s41580-020-0272-6

553
554
555
556

23. Li D, Cao R, Li Q, Yang Y, Tang A, Zhang J, et al. Nucleolus assembly impairment leads to two-cell transcriptional repression via NPM1-mediated PRC2 recruitment. Nature Structural & Molecular Biology 2023 30:7 [Internet]. 2023 May 18 [cited 2025 Sep 13];30(7):914-25. Available from: https://www.nature.com/articles/s41594-023-01003-w

557
558
559
560

24. Hu S, Eberhard L, Chen J, Love JC, Butler JP, Fredberg JJ, et al. Mechanical anisotropy of adherent cells probed by a three-dimensional magnetic twisting device. Am J Physiol Cell Physiol [Internet]. 2004 Nov [cited 2025 Aug 30];287(5 56-5):1184-91. Available from: www.ajpcell.org

561
562
563

25. Hu S, Chen J, Butler JP, Wang N. Prestress mediates force propagation into the nucleus. Biochem Biophys Res Commun [Internet]. 2005;329:423-8. Available from: www.elsevier.com/locate/ybbrc
564 26. Caragine CM, Haley SC, Zidovska A. Nucleolar dynamics and interactions with nucleoplasm in living cells. Elife. 2019 Nov 1;8.

566 27. Feric M, Vaidya N, Harmon TS, Mitrea DM, Zhu L, Richardson TM, et al. Coexisting liquid phases underlie nucleolar sub-compartments. Cell [Internet]. 2016 Jun 16 [cited 2025 Sep 9];165(7):1686. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5127388/

569 28. Lafontaine DLJ. Birth of Nucleolar Compartments: Phase Separation-Driven Ribosomal RNA Sorting and Processing. Mol Cell [Internet]. 2019 Dec 5 [cited 2025 Sep 9];76(5):694-6. Available from: https://www.cell.com/action/showFullText?pii=S1097276519308639

572 29. Andersen JS, Lyon CE, Fox AH, Leung AKL, Lam YW, Steen H, et al. Directed proteomic analysis of the human nucleolus. Current Biology [Internet]. 2002 Jan 8 [cited 2025 Sep 9];12(1):1-11. Available from: https://www.cell.com/action/showFullText?pii=S0960982201006509

575 30. Falahati H, Wieschaus E. Independent active and thermodynamic processes govern the nucleolus assembly in vivo. Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):1335-40.

577 31. Ferrolino MC, Mitrea DM, Michael JR, Kriwacki RW. Compositional adaptability in NPM1-SURF6 scaffolding networks enabled by dynamic switching of phase separation mechanisms. Nature Communications 2018 9:1 [Internet]. 2018 Nov 29 [cited 2025 Sep 9];9(1):1-11. Available from: https://www.nature.com/articles/s41467-018-07530-1

581 32. Mitrea DM, Cika JA, Guy CS, Ban D, Banerjee PR, Stanley CB, et al. Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA. Elife [Internet]. 2016 Feb 2 [cited 2025 Sep 9];5(FEBRUARY2016):e13571. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC4786410/

585 33. Bizhanova A, Kaufman PD. Close to the edge: heterochromatin at the nucleolar and nuclear peripheries.

587 34. Bersaglieri C, Santoro R. Genome Organization in and around the Nucleolus. 2019 [cited 2025 Sep 10]; Available from: www.mdpi.com/journal/cells

589 35. Vertii A, Ou J, Yu J, Yan A, Pagès H, Liu H, et al. Two contrasting classes of nucleolus-associated domains in mouse fibroblast heterochromatin. Genome Res [Internet]. 2019 [cited 2025 Sep 10];29(8):1235-49. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6673712/

592 36. Gupta S, Bersaglieri C, Bär D, Raingeval M, Schaab L, Santoro R. The nucleolar granular component mediates genome-nucleolus interactions and establishes their repressive chromatin states. Mol Cell [Internet]. 2025 Jun 5 [cited 2025 Sep 10];85(11):2165-2175.e6. Available from: https://www.cell.com/action/showFullText?pii=S1097276525004095

596 37. Buchwalter A, Hetzer MW. Nucleolar expansion and elevated protein translation in premature aging. Nature Communications 2017 8:1 [Internet]. 2017 Aug 30 [cited 2025 Sep 10];8(1):1-13. Available from: https://www.nature.com/articles/s41467-017-00322-z

599 38. Gupta A Sen, Sengupta K. Lamin B2 Modulates Nucleolar Morphology, Dynamics, and Function. Mol Cell Biol [Internet]. 2017 Dec 1 [cited 2025 Sep 10];37(24):e00274-17. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5705821/

602 39. Malhas A, Lee CF, Sanders R, Saunders NJ, Vaux DJ. Defects in lamin B1 expression or processing affect interphase chromosome position and gene expression. J Cell Biol [Internet].
604 2007 Feb 26 [cited 2025 Sep 10];176(5):593. Available from:
605 https://pmc.ncbi.nlm.nih.gov/articles/PMC2064018/

606 40. Azkanaz M, López AR, De Boer B, Huiting W, Angrand PO, Vellenga E, et al. Protein quality control in the nucleolus safeguards recovery of epigenetic regulators after heat shock. Elife [Internet]. 2019 Jun 1 [cited 2025 Sep 10];8. Available from:
607
608
609 https://pubmed.ncbi.nlm.nih.gov/31199242/

610 41. Potapova TA, Unruh JR, Conkright-Fincham J, Banks CA, Florens L, Schneider DA, et al. Distinct states of nucleolar stress induced by anticancer drugs. 2023;12:88799.
611

612 42. Snyers L, Laffer S, Löhnert R, Weipoltshammer K, Schöfer C. CX-5461 causes nucleolar compaction, alteration of peri- and intranucleolar chromatin arrangement, an increase in both heterochromatin and DNA damage response. Sci Rep [Internet]. 2022 Dec 1 [cited 2025 Sep 10];12(1). Available from: https://pubmed.ncbi.nlm.nih.gov/35978024/

616 43. Rolicka A, Guo Y, Gañez Zapater A, Tariq K, Quin J, Vintermist A, et al. The chromatin-remodeling complexes B-WICH and NuRD regulate ribosomal transcription in response to glucose. The FASEB Journal [Internet]. 2020 Aug 1 [cited 2025 Sep 10];34(8):10818-34. Available from: https://onlinelibrary.wiley.com/doi/full/10.1096/fj.202000411R

620 44. Velichko AK, Petrova N V., Luzhin A V., Strelkova OS, Ovsyannikova N, Kireev II, et al. Hypoosmotic stress induces R loop formation in nucleoli and ATR/ATM-dependent silencing of nucleolar transcription. Nucleic Acids Res [Internet]. 2019 Jul 26 [cited 2025 Sep 10];47(13):6811-25. Available from: https://pubmed.ncbi.nlm.nih.gov/31114877/

624 45. Cheng HH, Roggeveen J V., Wang H, Stone HA, Shi Z, Brangwynne CP. Micropipette aspiration reveals differential RNA-dependent viscoelasticity of nucleolar subcompartments. Proc Natl Acad Sci U S A [Internet]. 2025 Jun 3 [cited 2025 Aug 31];122(22). Available from:
625
626
627 https://doi.org/10.1073/pnas.2407423122

628 46. Riback JA, Eeftens JM, Lee DSW, Quinodoz SA, Donlic A, Orlovsky N, et al. Viscoelasticity and advective flow of RNA underlies nucleolar form and function. Mol Cell [Internet]. 2023 Sep 7 [cited 2025 Sep 14];83(17):3095-3107.e9. Available from:
629
630
631 https://pubmed.ncbi.nlm.nih.gov/37683610/

632 47. Zhu L, Richardson TM, Wacheul L, Wei MT, Feric M, Whitney G, et al. Controlling the material properties and rRNA processing function of the nucleolus using light. Proc Natl Acad Sci U S A [Internet]. 2019 Aug 27 [cited 2025 Sep 9];116(35):17330-5. Available from:
633
634
635 www.pnas.org/cgi/doi/10.1073/pnas.1903870116

636 48. Yang K, Wang M, Zhao Y, Sun X, Yang Y, Li X, et al. A redox mechanism underlying nucleolar stress sensing by nucleophosmin. Nature Communications 2016 7:1 [Internet]. 2016 Nov 25 [cited 2025 Sep 14];7(1):1-16. Available from:
637
638
639 https://www.nature.com/articles/ncomms13599

640 49. Yang K, Yang J, Yi J. Nucleolar Stress: hallmarks, sensing mechanism and diseases. Cell Stress [Internet]. 2018 Jun 1 [cited 2025 Sep 13];2(6):125. Available from:
641
642 https://pmc.ncbi.nlm.nih.gov/articles/PMC6551681/

643 50. Shav-Tal Y, Blechman J, Darzacq X, Montagna C, Dye BT, Patton JG, et al. Dynamic Sorting of Nuclear Components into Distinct Nucleolar Caps during Transcriptional Inhibition. Mol Biol
645 Cell [Internet]. 2005 May [cited 2025 Sep 14];16(5):2395. Available from:
646 https://pmc.ncbi.nlm.nih.gov/articles/PMC1087244/

647 51. Louvet E, Junéra HR, Le Panse S, Hernandez-Verdun D. Dynamics and compartmentation of the nucleolar processing machinery. Exp Cell Res. 2005 Apr 1;304(2):457-70.

649 52. Haaf T, Ward DC. Inhibition of RNA polymerase II transcription causes chromatin decondensation, loss of nucleolar structure, and dispersion of chromosomal domains. Exp Cell Res [Internet]. 1996 Apr 10 [cited 2025 Sep 14];224(1):163-73. Available from:
650
651
652 https://pubmed.ncbi.nlm.nih.gov/8612682/

653 53. Audas TE, Audas DE, Jacob MD, Ho JJD, Khacho M, Wang M, et al. Adaptation to Stressors by Systemic Protein Amyloidogenesis. Dev Cell [Internet]. 2016 Oct 24 [cited 2025 Sep 14];39(2):155. Available from: https://PMC.ncbi.nlm.nih.gov/articles/PMC5098424/

656 54. Latonen L, Moore HM, Bai B, Jäämaa S, Laiho M. Proteasome inhibitors induce nucleolar aggregation of proteasome target proteins and polyadenylated RNA by altering ubiquitin availability. Oncogene 2011 30:7 [Internet]. 2010 Oct 18 [cited 2025 Sep 14];30(7):790-805.
657
658
659 Available from: https://www.nature.com/articles/onc2010469

660 55. Gavrilova AA, Neklesova M V., Zagryadskaya YA, Kuznetsova IM, Turoverov KK, Fonin A V. Stress-Induced Evolution of the Nucleolus: The Role of Ribosomal Intergenic Spacer (rIGS) Transcripts. Biomolecules 2024, Vol 14, Page 1333 [Internet]. 2024 Oct 20 [cited 2025 Sep 14];14(10):1333. Available from: https://www.mdpi.com/2218-273X/14/10/1333/htm

664 56. Kechagia Z, Roca-Cusachs P. Cytoskeletal safeguards: Protecting the nucleus from mechanical perturbations. Curr Opin Biomed Eng. 2023 Dec 1;28:100494.

666 57. Maurer M, Lammerding J. The Driving Force: Nuclear Mechanotransduction in Cellular Function, Fate, and Disease. Annu Rev Biomed Eng [Internet]. 2019 [cited 2025 Sep 14];21:443. Available from: https://PMC.ncbi.nlm.nih.gov/articles/PMC6815102/

669 58. Martin C, Chen S, Maya-Mendoza A, Lovric J, Sims PFG, Jackson DA. Lamin B1 maintains the functional plasticity of nucleoli. J Cell Sci [Internet]. 2009 May 15 [cited 2025 Sep 2];122(10):1551-62. Available from: https://dx.doi.org/10.1242/jcs.046284

672 59. Stephens AD, Liu PZ, Banigan EJ, Almassalha LM, Backman V, Adam SA, et al. Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins. Mol Biol Cell [Internet]. 2018 Jan 15 [cited 2025 Sep 4];29(2):220-33. Available from:
673
674
675 https://search.library.newschool.edu/discovery/fulldisplay/cdi_pubmedcentral_primary_oai_pubmedcentral.nih_gov_5909933/01NYU_TNS:TNS

677 60. Matsumoto A, Sakamoto C, Matsumori H, Katahira J, Yasuda Y, Yoshidome K, et al. Loss of the integral nuclear envelope protein SUN1 induces alteration of nucleoli. Nucleus [Internet]. 2016 Mar 1 [cited 2025 Sep 4];7(1):68. Available from:
678
679
680 https://PMC.ncbi.nlm.nih.gov/articles/PMC4916878/

681 61. Zhao JZ, Xia J, Brangwynne CP. Chromatin compaction during confined cell migration induces and reshapes nuclear condensates. Nature Communications. 2024 Dec 1;15(1).

683 62. Strom AR, Kim Y, Zhao H, Chang YC, Orlovsky ND, Košmrlj A, et al. Condensate interfacial forces reposition DNA loci and probe chromatin viscoelasticity. Cell. 2024 Sep 19;187(19):5282-5297.e20.
686

63.

687

688

689

Zhao H, Strom AR, Eeftens JM, Haataja M, Košmrlj A, Brangwynne CP. Condensate-driven chromatin organization via elastocapillary interactions. bioRxiv [Internet]. 2025 Jun 15 [cited 2025 Sep 14];2025.06.12.659369. Available from: https://www.biorxiv.org/content/10.1101/2025.06.12.659369v1

690

64.

691

692

693

Dehingia B, Milewska-Puchała M, Janowski M, Rafiee MR, Abbas M, Piotrowska A, et al. RNA-binding proteins mediate the maturation of chromatin topology during differentiation. Nature Cell Biology 2025 27:9 [Internet]. 2025 Sep 8 [cited 2025 Sep 14];27(9):1510–25. Available from: https://www.nature.com/articles/s41556-025-01735-5

694

65.

695

696

Pundel OJ, Blowes LM, Connelly JT. Extracellular Adhesive Cues Physically Define Nucleolar Structure and Function. 2022 [cited 2025 Aug 21]; Available from: https://doi.org/10.1002/advs.202105545

697

66.

698

699

Florence Flick Jaecker, José A. Almeida, Carly M. Krull, Amit Pathak. Nucleoli in epithelial cell collectives respond to tumorigenic, spatial, and mechanical cues. MBoC [Internet]. 2022 [cited 2025 Aug 21];33(11). Available from: https://pubmed.ncbi.nlm.nih.gov/35830599/

700

701

702

Zhuang Y, Guo X, Razorenova O V., Miles CE, Zhao W, Shi X. Coaching ribosome biogenesis from the nuclear periphery. bioRxiv [Internet]. 2024 Jun 22 [cited 2025 Sep 3];2024.06.21.597078. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11212990/

703

68.

704

705

706

Brangwynne CP, Mitchison TJ, Hyman AA. Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes. Proc Natl Acad Sci U S A [Internet]. 2011 Mar 15 [cited 2025 Sep 3];108(11):4334–9. Available from: www.pnas.org/cgi/doi/10.1073/pnas.1017150108

707

69.

708

709

710

Banerjee DS, Chigumira T, Lackner RM, Kratz JC, Chenoweth DM, Banerjee S, et al. Interplay of condensate material properties and chromatin heterogeneity governs nuclear condensate ripening. bioRxiv [Internet]. 2024 Aug 21 [cited 2025 Sep 14];2024.05.07.593010. Available from: https://www.biorxiv.org/content/10.1101/2024.05.07.593010v2

711

70.

712

713

714

Xia J, Zhao JZ, Strom AR, Brangwynne CP. Chromatin heterogeneity modulates nuclear condensate dynamics and phase behavior. Nature Communications 2025 16:1 [Internet]. 2025 Jul 11 [cited 2025 Sep 14];16(1):1–16. Available from: https://www.nature.com/articles/s41467-025-60771-9

715

71.

716

717

Shin Y, Chang YC, Lee DSW, Berry J, Sanders DW, Ronceray P, et al. Liquid nuclear condensates mechanically sense and restructure the genome. Cell [Internet]. 2018 Nov 29 [cited 2025 Sep 14];175(6):1481. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6724728/

718

72.

719

Condeelis J, Singer RH. How and why does β-actin mRNA target? Biol Cell. 2005 Jan;97(1):97–110.

720

73.

721

722

723

Dermit M, Dodel M, Lee FCY, Azman MS, Schwenzer H, Jones JL, et al. Subcellular mRNA Localization Regulates Ribosome Biogenesis in Migrating Cells. Dev Cell [Internet]. 2020 Nov 9 [cited 2025 Sep 1];55(3):298-313.e10. Available from: https://pubmed.ncbi.nlm.nih.gov/33171110/

724

74.

725

726

727

Shim MS, Nettesheim A, Hirt J, Liton PB. The autophagic protein LC3 translocates to the nucleus and localizes in the nucleolus associated to NUFIP1 in response to cyclic mechanical stress. Autophagy [Internet]. 2020 [cited 2025 Sep 8];16. Available from: https://doi.org/10.1080/15548627.2019.1662584
728
729
730

75. Tancioni I, Miller NLG, Uryu S, Lawson C, Jean C, Chen XL, et al. FAK activity protects nucleostemin in facilitating breast cancer spheroid and tumor growth. Breast Cancer Research. 2015 Mar 28;17(1).

731
732
733
734

76. Blonski S, Aureille J, Badawi S, Recho P, Guilluy C, Dolega Correspondence ME. Direction of epithelial folding defines impact of mechanical forces on epithelial state. DEVCEL [Internet]. 2021 [cited 2025 Sep 9];56:3222-3234.e6. Available from: https://doi.org/10.1016/j.devcel.2021.11.008

735
736
737
738

77. Zhu J, Liu L, Lin R, Guo X, Yin J, Xie H, et al. RPL35 downregulated by mechanical overloading promotes chondrocyte senescence and osteoarthritis development via Hedgehog-Gli1 signaling. J Orthop Translat [Internet]. 2024 [cited 2025 Sep 8];45:226-35. Available from: https://doi.org/10.1016/j.jot.2024.01.003

739
740
741
742

78. Al Jord A, Letort G, Chanet S, Tsai FC, Antoniewski C, Eichmuller A, et al. Cytoplasmic forces functionally reorganize nuclear condensates in oocytes. Nature Communications 2022 13:1 [Internet]. 2022 Aug 29 [cited 2025 Sep 15];13(1):1-19. Available from: https://www.nature.com/articles/s41467-022-32675-5

743
744
745
746

79. Nakada S, Ogasawara R, Kawada S, Maekawa T, Ishii N. Correlation between Ribosome Biogenesis and the Magnitude of Hypertrophy in Overloaded Skeletal Muscle. PLoS One [Internet]. 2016 Jan 1 [cited 2025 Sep 15];11(1):e0147284. Available from: https://PMC.ncbi.nlm.nih.gov/articles/PMC4732984/

747
748
749

80. Montanaro L, Treré D, Derenzini M. Nucleolus, Ribosomes, and Cancer. Am J Pathol [Internet]. 2008 [cited 2025 Sep 15];173(2):301. Available from: https://PMC.ncbi.nlm.nih.gov/articles/PMC2475768/

750
751
752
753

81. Wang X, Liu R, Zhou L, Liu T, Wu H, Chen T, et al. Filamentous Actin in the Nucleus in Triple-Negative Breast Cancer Stem Cells: A Key to Drug-Induced Nucleolar Stress and Stemness Inhibition? J Cancer [Internet]. 2024 [cited 2025 Sep 15];15(17):5636. Available from: https://PMC.ncbi.nlm.nih.gov/articles/PMC11414619/

754
755
756
757
758

82. Thelen N, Defourny J, Lafontaine DLJ, Thiry M. Visualization of chromatin in the yeast nucleus and nucleolus using hyperosmotic shock. Int J Mol Sci [Internet]. 2021 Feb 1 [cited 2025 Sep 15];22(3):1-11. Available from: https://www.researchgate.net/publication/348748678_Visualization_of_Chromatin_in_the_Yeast_Nucleus_and_Nucleolus_Using_Hyperosmotic_Shock

759
760
761
762

83. Jin X, Tanaka H, Jin M, Fujita K, Homma H, Inotsume M, et al. PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions. Nature Communications 2023 14:1 [Internet]. 2023 Jan 4 [cited 2025 Sep 7];14(1):1-20. Available from: https://www.nature.com/articles/s41467-022-35602-w

763
764
765
766

84. Yang L, Reece JM, Cho J, Bortner CD, Shears SB. The nucleolus exhibits an osmotically regulated gatekeeping activity that controls the spatial dynamics and functions of nucleolin. Journal of Biological Chemistry [Internet]. 2008 Apr 25 [cited 2025 Sep 9];283(17):11823-31. Available from: https://www.jbc.org/action/showFullText?pii=S0021925820619767

767
768
769

85. Burg MB, Ferraris JD. Intracellular Organic Osmolytes: Function and Regulation. J Biol Chem [Internet]. 2008 Mar 21 [cited 2025 Sep 15];283(12):7309. Available from: https://PMC.ncbi.nlm.nih.gov/articles/PMC2276334/
770 86. De Nadal E, Posas F. The HOG pathway and the regulation of osmoadaptive responses in yeast. FEMS Yeast Res [Internet]. 2022 [cited 2025 Sep 15];22(1):foac013. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8953452/

773 87. Kim RD, Darling CE, Cerwenka H, Chari RS. Hypoosmotic Stress Activates p38, ERK 1 and 2, and SAPK/JNK in Rat Hepatocytes. Journal of Surgical Research. 2000 May 1;90(1):58-66.

775 88. Wang F, Bonam SR, Schall N, Kuhn L, Hammann P, Chaloin O, et al. Blocking nuclear export of HSPA8 after heat shock stress severely alters cell survival. Sci Rep [Internet]. 2018 Dec 1 [cited 2025 Sep 29];8(1):16820. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6235846/

778 89. Sloan KE, Bohnsack MT, Watkins NJ. The 5S RNP Couples p53 Homeostasis to Ribosome Biogenesis and Nucleolar Stress. Cell Rep. 2013 Oct 17;5(1):237-47.

780 90. Lirussi L, Antoniali G, Vascotto C, D'Ambrosio C, Poletto M, Romanello M, et al. Nucleolar accumulation of APE1 depends on charged lysine residues that undergo acetylation upon genotoxic stress and modulate its BER activity in cells. Mol Biol Cell [Internet]. 2012 Oct 15 [cited 2025 Oct 1];23(20):4079. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC3469522/

785 91. Vascotto C, Fantini D, Romanello M, Cesaratto L, Deganuto M, Leonardi A, et al. APE1/Ref-1 Interacts with NPM1 within Nucleoli and Plays a Role in the rRNA Quality Control Process. Mol Cell Biol [Internet]. 2009 Apr 1 [cited 2025 Sep 30];29(7):1834. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC2655621/

789 92. Saporita AJ, Chang HC, Winkeler CL, Apicelli AJ, Kladney RD, Wang J, et al. RNA helicase DDX5 is a p53-independent target of ARF that participates in ribosome biogenesis.

791 93. Damalas A, Velimezi G, Kalaitzakis A, Liontos M, Papavassiliou AG, Gorgoulis V, et al. Loss of p14ARF confers resistance to heat shock- and oxidative stress-mediated cell death by upregulating β-catenin. Int J Cancer [Internet]. 2011 Apr 15 [cited 2025 Sep 30];128(8):1989-95. Available from: https://onlinelibrary-wiley.com.proxy.insermbiblio.inist.fr/doi/full/10.1002/ijc.25510