Mechanosensitive nuclear checkpoint: nuclear envelope as a sensor of chromosomal instability and driver of cell fate

Abstract

The nuclear envelope (NE) is a dynamic, mechanosensitive structure that functions as a protective barrier for the genome and serves as a checkpoint responding to external stimuli. It plays a critical role in maintaining genomic stability and regulating cell fate. This review synthesizes recent research highlighting the role of NE as a mechanical checkpoint in ensuring accurate chromosome segregation, regulating cell cycle progression, and contributing to cancer development. Chromosome mis-segregation during cell division is a major driver of aneuploidy, a condition closely associated with genomic instability and cellular transformation. The role of NE in chromatin organization and gene expression regulation is also discussed, underscoring its importance in cell differentiation and identity.

Graphical abstract

Accurate chromosome segregation is fundamental to maintaining genomic stability. A recent study provides compelling evidence that chromosome mis-segregation activates cell cycle arrest via a mechanosensitive nuclear envelope (NE) checkpoint.¹ Such segregation errors lead to NE dysfunction, rapidly triggering the p53/p21 ​cell cycle checkpoint pathway, which is essential for preserving genomic integrity. This study highlights the role of NE as a mechanosensitive structure capable of detecting and responding to mechanical perturbations induced by chromosome mis-segregation. It further identifies mTORC2 and ATR as key sensors that detect mechanical changes in the NE and initiate the p53/p21 signaling cascade. These findings underscore the crucial role of NE in cell cycle regulation and suggest potential targets for cancer therapy.

Chromosome mis-segregation during cell division is a major contributor to aneuploidy, a condition closely associated with genomic instability and cellular transformation, and commonly observed in various cancers. Utilizing a controlled chromosome mis-segregation system, researchers demonstrated that such errors induce nuclear deformation and softening. These changes activate the p53/p21 pathway during late mitosis, leading to cell cycle arrest. The nuclear deformation is likely driven by aberrant interactions between mis-segregated chromosomes and the NE, compromising its mechanical integrity (Fig. 1). The study further identified mTORC2 and ATR as mechanosensors that detect these structural perturbations and trigger pathway activation.¹

Fig. 1.

Schematic of the nuclear envelope determines cell fate. Chromosome mis-segregation leads to nuclear envelope dysfunction and tension decrease, which quickly activates the p53/p21 pathway, probably induces cellular transformation and cancer progression. Nuclear envelop works as a mechanosensitive checkpoint during this progress.

This study reveals a new mechanism by which chromosome mis-segregation induces cell cycle arrest via NE mechanosensitivity, enhancing our understanding of cell cycle regulation and suggesting promising targets for cancer therapy with major clinical implications.

The NE, a dynamic interface that separates the nucleus from cytoplasm, plays multifaceted roles in regulating cell fate through its structural, mechanical, and regulatory functions. Emerging research highlights its critical involvement in chromatin organization, genome stability, and cancer progression. During interphase, the NE anchors chromatin via lamina-associated domains and NE transmembrane proteins, shaping the three-dimensional (3D) genome architecture to modulate transcriptional programs.² These spatial interactions maintain heterochromatin positioning and influence cell-type-specific gene expression, thereby linking NE integrity to cell differentiation and identity.

During cell division, the NE undergoes critical dynamic remodeling. In the prophase of mitosis, the NE disassembles, allowing chromosomes to interact with spindle microtubules and segregate into daughter nuclei.³ NE reassembly is tightly coordinated with chromatin dynamics to ensure accurate chromosome segregation. In mouse embryos, the establishment of nuclear organization is orchestrated by multiple epigenetic pathways.⁴ Disruptions in these processes result in chromosome segregation errors, micronucleus formation, and chromosomal instability—all hallmarks of cancer. Furthermore, NE rupture can directly induce DNA damage and exacerbate genomic instability by impairing DNA repair mechanisms and elevating replication stress.

NE morphology and function profoundly influence cell fate. Cancer cells often exhibit abnormal NE morphology, including pleomorphic nuclei, nuclear grooves, and chromatin configuration abnormalities.⁵ These alterations not only serve as important diagnostic markers for cancer but may also directly contribute to tumorigenesis. Expression levels of NE proteins and morphological alterations in NE hold promise as potential biomarkers for early cancer detection and prognostic evaluation. For instance, low lamin A/C expression is associated with increased invasiveness and poor breast cancer prognosis, while the absence or mutation of emerin compromises nuclear mechanical stability and mechanotransduction, thereby influencing tumor cell behavior.⁶ Additionally, compounds targeting NE-related signaling pathways also show promise. For example, WYC-209 induces apoptosis in tumor repopulating cells by modulating cellular traction forces and chromatin condensation, thereby overcoming cancer stem cell drug resistance. This strategy offers new insights into the treatment of drug-resistant cancer.⁷

NE plays a central role in genome organization by interacting with chromatin to regulate gene expression. For instance, the NE protein LAP2β transmits mechanical forces to chromatin domains, promoting chromatin relaxation and upregulation of gene expression.⁸ In Drosophila, detachment of specific genes, such as hunchback, from the NE reduces their silencing.⁹ Rashid et al. used microinjection to introduce ferrimagnetic nanoparticles coated with anti-histone H2B into the nucleus, where they specifically bound to chromatin. The study revealed that both chromatin and the nucleoplasm retain a form of mechanical memory following exposure to mechanical forces.¹⁰ These spatial interactions maintain heterochromatin positioning and regulate cell-type-specific gene expression, thereby closely linking NE integrity to cell differentiation and identity.

The NE exhibits mechanosensitivity, enabling it to sense and respond to mechanical stimuli resulting from chromosome segregation errors or external stress. For instance, mechanical forces applied to the cell surface can be transmitted through the cytoskeleton to the NE, directly stretching chromatin and thereby upregulating gene expression.¹¹ Mechanical forces also induce emerin accumulation on the outer nuclear membrane, leading to improper anchoring of heterochromatin to the nuclear lamina and a transition from H3K9me2/3 to H3K27me3.¹² Nucleus deformation and oscillations in NE tension can regulate cell spreading and migration. Additionally, expression levels of NE proteins such as lamin A/C and emerin modulate nuclear deformability and mechanical stability, influencing the cell's mechanical adaptation. However, aberrant expression of NE proteins and morphological alterations in the NE are closely associated with cancer progression. Regulation of nuclear mechanical properties by lamins also directly influences cell motility. For instance, high lamin A/C expression increases nuclear stiffness, which can hinder migration through narrow interstitial gaps in 3D environments.¹³ Moreover, mechanical forces can alter the conformation of nuclear pore complexes, affecting NE integrity and cellular mechanotransduction.¹⁴

NE rupture can induce DNA damage not only in tumor cells but also in other cell types and tissues subjected to mechanical compression. Mechanical stimuli can elicit DNA damage, which is detected via the NE and lamins, thereby activating DNA repair pathways.¹⁵ However, such damage may also result in cell death, senescence, or mutations, ultimately compromising genomic stability. In contrast, the absence or mutation of emerin can impair the mechanical stability and mechanotransduction capacity of the nucleus, thereby influencing tumor cell behavior. NE rupture activates a DNA damage response, and cells counteract this by recruiting the ESCRT-III complex to repair the rupture, thereby limiting DNA damage and preventing cell death.⁶ However, disrupting the physical connection between the NE and cytoskeleton—by interfering with the LINC complex—can prevent NE rupture, reduce DNA damage, and restore myofiber viability and contractility in lamin A/C-deficient cells.¹⁶ Nuclear pore complexes (NPCs) also play a key role in responding to mechanical changes during cell differentiation. Cryo-electron tomography studies comparing NPC structure in wild-type and Nup133-deficient cell lines have shown that Nup133 deficiency compromises NE integrity, thereby increasing DNA damage.¹⁷

Alterations in the NE also offer new strategies for tissue engineering and regenerative medicine. For instance, NE proteins and chromatin structure play critical roles in cell reprogramming. Studies have shown that specific combinations of transcription factors, such as OSKM and GETM, can reorganize the 3D chromatin structure to activate gene expression, thereby redefining cell fate. These transcription factors efficiently activate target genes by binding to specific topological structures of nucleosomes, driving cellular reprogramming.¹⁸ Elevated lamin A expression enhances cellular responsiveness to the extracellular matrix, thereby promoting cell differentiation.¹⁹ For example, targeted cytokine exposure and mechanical stimulation can directly transdifferentiate fibroblasts into valvular endothelial cells without using viruses or induced pluripotent stem cells (iPSCs). This approach avoids potential risks associated with viral and iPSC methods, providing a promising avenue for tissue engineering and regenerative therapies.²⁰

The NE is more than a structural barrier enclosing the genome—it serves as a key regulator of cell fate. Its dynamic architecture and mechanosensitivity enable it to respond to genome movement while anchoring chromatin. Changes in the NE substantially influence gene expression, cell cycle progression, differentiation, and cancer development. Targeting the mechanical properties of NE or the dynamic regulation of its associated proteins presents new insights for cancer treatment, regenerative medicine, and immunotherapy. Additionally, exploring the role of mechanotransduction in cell fate determination will be crucial. Mechanical stimulation, involved in many biological activities such as tissue development, regeneration, and remodeling, also contributes to immunotherapy resistance by influencing the anti-tumor immunity cascade. Future research should aim to elucidate the molecular mechanisms underlying the mechanosensitive checkpoint of NE, its interactions with chromatin, and its potential therapeutic applications, particularly in the cancer and regenerative contexts.

CRediT authorship contribution statement

Chenyang Ji: Writing – original draft. Junwei Chen: Writing – review & editing, Funding acquisition. Fuxiang Wei: Writing – review & editing, Writing – original draft, Funding acquisition.

Ethical approval

This study does not involve any experiments with human participants or animals conducted by the authors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.