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Results for “nuclear pore complex”

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PubMed2023

Super-enhancer trapping by the nuclear pore via intrinsically disordered regions of proteins in squamous cell carcinoma cells.

Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within the nucleus remains unknown. The nuclear pore complex (NPC) may tether SEs to the nuclear pore where RNA export rates are maximal. Here, we report that NUP153, a component of the NPC, anchors SEs to the NPC and enhances TP63 expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between the intrinsically disordered regions (IDRs) of NUP153 and the coactivator BRD4. Silencing of NUP153 excludes SEs from the nuclear periphery, decreases TP63 expression, impairs cellular growth, and induces epidermal differentiation of squamous cell carcinoma. Overall, this work reveals the critical roles of NUP153 IDRs in the regulation of SE localization, thus providing insights into a new layer of gene regulation at the epigenomic and spatial level.

Humans↗

PubMed2024

MX2 forms nucleoporin-comprising cytoplasmic biomolecular condensates that lure viral capsids.

Human myxovirus resistance 2 (MX2) can restrict HIV-1 and herpesviruses at a post-entry step through a process requiring an interaction between MX2 and the viral capsids. The involvement of other host cell factors, however, remains poorly understood. Here, we mapped the proximity interactome of MX2, revealing strong enrichment of phenylalanine-glycine (FG)-rich proteins related to the nuclear pore complex as well as proteins that are part of cytoplasmic ribonucleoprotein granules. MX2 interacted with these proteins to form multiprotein cytoplasmic biomolecular condensates that were essential for its anti-HIV-1 and anti-herpes simplex virus 1 (HSV-1) activity. MX2 condensate formation required the disordered N-terminal region and MX2 dimerization. Incoming HIV-1 and HSV-1 capsids associated with MX2 at these dynamic cytoplasmic biomolecular condensates, preventing nuclear entry of their viral genomes. Thus, MX2 forms cytoplasmic condensates that likely act as nuclear pore decoys, trapping capsids and inducing premature viral genome release to interfere with nuclear targeting of HIV-1 and HSV-1.

Humans↗

PubMed2025

Nuclear basket proteins Nup2 and Mlp1 drive heat shock-induced 3D genome restructuring downstream of transcriptional activation.

The nuclear pore complex (NPC), a multisubunit complex located within the nuclear envelope, regulates RNA export and the import and export of proteins. Here we address the role of the NPC in driving thermal stress-induced 3D genome repositioning of Heat Shock Responsive (HSR) genes in budding yeast. We found that two nuclear basket proteins, Nup2 and Mlp1, although dispensable for NPC integrity, are required for driving HSR genes into coalesced chromatin clusters, consistent with their strong, heat shock-dependent recruitment to HSR gene regulatory and coding regions. HSR gene clustering occurs predominantly within the nucleoplasm and is independent of the essential scaffold-associated proteins Nup1 and Nup145. Notably, acute double depletion of Nup2 and Mlp1 has little effect on the formation of Heat Shock Factor 1 (Hsf1)-containing transcriptional condensates, Hsf1 and Pol II recruitment to HSR genes, or HSR mRNA abundance. Our results define a 3D genome restructuring role for nuclear basket proteins extrinsic to the NPC and downstream of HSR gene activation.

3D genome architecture↗

PubMed2025

Temporal gating of nuclear import: How Merkel cell polyomavirus exploits the cell cycle for nuclear entry.

Merkel cell polyomavirus (MCPyV) is a small, DNA tumor virus that is causally linked to an aggressive form of human skin cancer called Merkel cell carcinoma. MCPyV is the only polyomavirus definitively shown to cause cancer in humans, yet little is known about how it establishes infection in target cells. In this study, we report an unconventional mechanism by which MCPyV enters the host cell nucleus, where viral genome replication occurs. We demonstrate that, unlike other known polyomaviruses, MCPyV does not require the nuclear pore complex during entry. Instead, it takes advantage of cell cycle-dependent nuclear envelope breakdown to deliver its genetic material into the nucleus. We further show that the VP1 major capsid protein is sufficient to facilitate this process. Overall, our findings reveal a novel mechanism of polyomavirus nuclear entry and provide insight into the diverse mechanisms that these viruses use to cause infection.

Merkel cell polyomavirus↗

PubMed2025

Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al., Curr. Biol. 26, 2651-2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al., Nucleus 9, 258-275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al., Cancer Res. Commun. 2, 503-517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.

Lamin Type A↗

PubMed2026

ELYS associates with distinct DNA sequence environments during post-mitotic nuclear pore reassembly.

Nuclear pore complexes (NPCs) contribute to genome organization and cell identity, yet how post-mitotic NPC assembly is coordinated with chromatin architecture remains unclear. Here, we show that the nucleoporin ELYS preferentially associates with chromatin regions displaying distinct intrinsic DNA sequence features that are not explained by the repressive histone marks examined here. ELYS-bound regions are enriched for AT-rich sequences, whereas ELYS binding at super-enhancer-associated loci shift toward GC-rich sequence composition, revealing distinct sequence environments. These findings indicate that ELYS localization is associated with distinct intrinsic DNA sequence features and suggest a mechanism by which nuclear pore-associated architecture restores transcriptional programs after mitosis.

Journal Article↗

PubMed2026

Signaling into the nucleus through the importin 7 pathway.

Importin 7 (IPO7) is a nuclear transport receptor of the β-karyopherin family that mediates the translocation of a broad spectrum of macromolecules, commonly referred to as cargoes. Discovered nearly three decades ago, IPO7 was initially identified as an import receptor for constitutive cellular cargoes, including histone H1 and ribosomal proteins, and was shown to function synergistically and partially redundantly with canonical receptors such as importin β1 and karyopherin β2. Over the past 15 years, however, accumulating evidence has established IPO7 as an important mediator of signal-dependent nuclear trafficking in response to extracellular stimuli, including cytokines, growth factors, and cellular stress. Thus, IPO7 has emerged as a versatile nuclear transport receptor that couples extracellular signaling to dynamic changes in nuclear composition and gene expression. Mechanistically, many IPO7 cargoes lack classical nuclear localization signals and instead contain noncanonical targeting motifs that directly engage IPO7. In several cases, phosphorylation-dependent conformational changes expose these motifs, promoting IPO7 binding and translocation through the nuclear pore complex. The expanding repertoire of IPO7 cargoes, including ERK, SMAD3, EGR1, GLI1, the glucocorticoid receptor, HIF-1α, YAP1, and RUNX2, highlights its prominent role at the interface of signaling and transcriptional control. Consistent with these functions, dysregulation of IPO7-mediated transport has been implicated in cancer, hypoxia, and other pathological states. Beyond cellular signaling, IPO7 also contributes to the nuclear trafficking of viral genomes and proteins. Here, we review the molecular mechanisms of IPO7-dependent nuclear import, emerging principles of cargo recognition, and pathways that regulate IPO7 activity during cellular signaling.

NLS↗

PubMed2025

Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [1]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [2]. Here, we investigate LMNA's role in small-cell lung cancer (SCLC), a highly aggressive malignancy characterized by extreme genomic instability [3, 4]. We demonstrate that LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA loss disrupts nuclear pore complex distribution, reducing phenylalanine-glycine (FG)-nucleoporin incorporation and impairing RNA export efficiency. Furthermore, we show that LMNA expression is epigenetically repressed by EZH2 during SCLC differentiation from neuroendocrine (NE) to non-NE states. Clinically, low LMNA levels correlate with significantly worse survival in SCLC patients. These findings uncover a novel role for LMNA in safeguarding genome integrity and shaping tumor heterogeneity, with broad implications for cancer and aging.

Biological Sciences↗

PubMed2026

Nucleoporins in Cancer: Functional Roles and Therapeutic Opportunities.

UNLABELLED: The nuclear pore complex (NPC) and its building-block proteins, nucleoporins (NUP), play fundamental roles in maintaining cellular fitness by regulating nucleocytoplasmic transport, chromatin and transcriptional activity, and genome stability. These core biological processes are critical for cancer cells, and thus, tumor-driven co-option of NUP-regulated functions has emerged as an important mechanism contributing to the pathogenesis of multiple malignancies. This review discusses how NUP dysregulation mechanistically contributes to tumor initiation and progression and how these insights open opportunities for innovative anticancer therapies, including using clinical-grade molecular glues that induce selective NUP degradation and pharmacologically inhibiting NPC-regulated epigenomic/transcriptomic signaling and nucleocytoplasmic transport. SIGNIFICANCE: Recent studies demonstrate that NUPs play fundamental roles in cancer pathogenesis by dysregulating key NPC functions and driving tumorigenesis and disease progression. NUPs and NPC-regulated mechanisms can be pharmacologically targeted, providing a strong rationale for developing much-needed innovative therapeutic strategies to combat cancer.

Journal Article↗

PubMed2025

KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.

UNLABELLED: NUP98 fusion oncoproteins (FO) are a hallmark of childhood acute myeloid leukemia. NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. In this study, we show that MYST family histone acetyltransferase (HAT) complex proteins, including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1, associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of KAT6A and KAT7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with menin inhibitor treatment, and was efficacious in menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r acute myeloid leukemia. SIGNIFICANCE: KAT6A and KAT7 associate with NUP98 FOs to drive leukemogenesis. Inhibition of their HAT activity is an effective therapeutic strategy in NUP98-r leukemias, including those resistant to menin inhibition. Moreover, combined KAT6A/7 and menin inhibition is synergistic, supporting clinical translation to improve outcomes for NUP98 FO-driven leukemias.

Humans↗