# NUP214 Gene: Structure, Function, and Clinical Significance ## Key Takeaways - NUP214 is a critical nucleoporin localized to the cytoplasmic face of the nuclear pore complex, essential for nucleocytoplasmic transport, particularly the terminal steps of mRNA export and protein import via its interaction with CRM1. - Aberrant *NUP214* rearrangements, specifically the *DEK–NUP214* fusion oncogene from t(6;9) in AML and the episomal *NUP214–ABL1* fusion in T-ALL, are recurrent drivers of hematological malignancies with distinct pathogenetic mechanisms and clinical implications. - NUP214 participates in cell cycle regulation and mitotic checkpoint function, forming a complex with MAD1 at kinetochores to ensure proper chromosome segregation, independent of its transport role. - The protein's structure features FG-repeat regions crucial for transport receptor binding and a C-terminal domain involved in CRM1 stabilization, with post-translational modifications like phosphorylation and O-GlcNAcylation modulating its function and interactions. - Pharmacological targeting of NUP214's interactions, particularly through CRM1 inhibitors (SINEs) like selinexor, and ABL1 kinase inhibitors in *NUP214–ABL1* T-ALL, represent key therapeutic strategies for NUP214-associated cancers. - NUP214 serves as a host dependency factor for viral infections, notably facilitating HIV-1 PIC nuclear import via Vpr interaction and Influenza A virus vRNP nuclear export through its CRM1-binding FG-repeats. --- ## Executive Summary & Key Metadata NUP214 (Nucleoporin 214) encodes a 214 kDa phenylalanine-glycine (FG)-repeat-containing nucleoporin that constitutes a critical structural and functional component of the nuclear pore complex (NPC). As a member of the cytoplasmic filament and central scaffold of the NPC, NUP214 serves as a docking platform for the nuclear transport receptor CRM1 (Exportin-1/XPO1) and participates in the terminal steps of nuclear mRNA export and protein import. Beyond its canonical transport functions, NUP214 is a recurrent target of chromosomal translocations in acute leukemias, most notably the t(6;9)(p23;q34) translocation generating the *DEK–NUP214* fusion oncogene, and the episomal amplification of *NUP214–ABL1* in T-cell acute lymphoblastic leukemia (T-ALL). This manual provides a comprehensive, biophysically grounded reference for the genomic architecture, structural biology, signaling integration, pathogenic mutation spectrum, host-pathogen interfaces, and pharmacogenomic landscape of NUP214. | **Attribute** | **Value** | |---|---| | HGNC Symbol | NUP214 | | UniProt Accession | P35658 | | Representative PDB ID | 5IJO (human NUP214–CRM1–RanBP2 complex) | | Chromosomal Locus | 9q34.13 (GRCh38: chr9:131,712,000–131,844,000) | | Primary Molecular Function | Nucleocytoplasmic transport; FG-repeat nucleoporin; CRM1 docking; mRNA export | | Disease & Pathology Associations | Acute myeloid leukemia (AML) with t(6;9); T-ALL with episomal *NUP214–ABL1*; susceptibility to viral infection (HIV-1, influenza) | | Protein Length | 2,090 amino acids (canonical isoform 1) | | Molecular Weight | ~214 kDa (predicted) | | Subcellular Localization | Nuclear pore complex, cytoplasmic face; nuclear envelope | --- ## 1. Genomic Locus, Chromosomal Organization & Isoforms ### 1.1 Chromosomal Coordinates and Gene Structure The *NUP214* gene is located on the long arm of chromosome 9 at band q34.13, a genomic region notable for its density of disease-associated loci, including *ABL1* (immediately telomeric) and *NOTCH1* (centromeric). The reference genome assembly (GRCh38) places *NUP214* between approximately 131,712,000 and 131,844,000 base pairs on the forward strand. The gene spans roughly 132 kilobases of genomic DNA and comprises 28 exons, with the translation initiation codon located in exon 2 and the stop codon in exon 28. The intron-exon boundaries follow canonical GT-AG splice donor-acceptor rules, with the exception of a rare non-canonical GC-AG splice site in intron 12 that is conserved across mammals. The promoter region of *NUP214* lacks a canonical TATA box but contains a CpG island spanning approximately 1.2 kb surrounding the transcription start site (TSS). This CpG island is hypomethylated across most normal tissues, consistent with housekeeping expression. Multiple transcription factor binding sites have been experimentally validated within the proximal promoter, including SP1, E2F1, and MYC. Chromatin immunoprecipitation (ChIP-seq) data from ENCODE reveal that the *NUP214* promoter is marked by H3K4me3 and H3K27ac in proliferating cells, while poised enhancer marks (H3K4me1) are found in an intronic region of intron 3, suggesting cell-type-specific regulatory plasticity. ### 1.2 Enhancer Elements and Long-Range Chromatin Interactions Hi-C and promoter capture Hi-C (pcHi-C) analyses in hematopoietic cells demonstrate that the *NUP214* promoter engages in long-range chromatin interactions with a distal enhancer element located approximately 250 kb telomeric, within the *ABL1* gene body. This interaction is dynamic and increases upon T-cell receptor (TCR) stimulation, correlating with a 2- to 3-fold upregulation of *NUP214* transcription. Additionally, a super-enhancer region at 9q34.13 has been identified in primary AML cells, which may contribute to the elevated NUP214 expression observed in leukemic blasts. The presence of a topologically associating domain (TAD) boundary between *NUP214* and *ABL1* is partially disrupted by the t(6;9) translocation, leading to aberrant enhancer-promoter rewiring that may influence fusion oncogene expression. ### 1.3 Alternative Splicing and Isoform Diversity The *NUP214* gene undergoes extensive alternative splicing, with at least six distinct transcript variants catalogued in Ensembl (ENST00000361321, ENST00000445372, ENST00000478543, ENST00000479762, ENST00000484562, ENST00000498334). The canonical transcript (ENST00000361321) encodes the full-length 2,090-amino-acid protein. Notable splice variants include: - **Isoform 2 (ENST00000445372):** Retains intron 5, introducing a premature stop codon. This transcript is predicted to undergo nonsense-mediated decay (NMD) and may serve a regulatory role in modulating NUP214 protein levels under cellular stress. - **Isoform 3 (ENST00000478543):** Skips exon 14, resulting in an in-frame deletion of 42 amino acids within the central coiled-coil domain. This isoform shows reduced binding affinity for CRM1 in vitro, suggesting that exon 14 encodes a critical interface for transport receptor interaction. - **Isoform 4 (ENST00000479762):** Uses an alternative 3' splice site in exon 21, adding 12 amino acids to the C-terminal region. This isoform is predominantly expressed in testis and may have specialized functions in germ cell nuclear transport. Quantitative RT-PCR across human tissues reveals that *NUP214* is ubiquitously expressed, with highest levels in thymus, bone marrow, and testis. Single-cell RNA-seq data from the Human Cell Atlas confirm broad expression across all hematopoietic lineages, with peak expression in proliferating progenitor cells. --- ## 2. 3D Protein Domain Architecture & Structural Biology ### 2.1 Domain Organization of NUP214 The NUP214 protein is a large, intrinsically disordered FG-repeat nucleoporin that adopts a modular architecture. From N-terminus to C-terminus, the following domains and structural features are recognized: | **Region** | **Residues (canonical)** | **Structural/Functional Features** | |---|---|---| | N-terminal domain | 1–200 | β-propeller-like fold; interacts with NUP88 (NUP96) and the cytoplasmic filament protein NUP358/RanBP2 | | FG-repeat region 1 | 200–700 | Multiple FG, FxFG, and GLFG motifs; mediates weak hydrophobic interactions with transport receptors (Karyopherins) | | Central coiled-coil domain | 700–1100 | α-helical coiled-coil; mediates NUP214 dimerization and interaction with NUP62 complex | | FG-repeat region 2 | 1100–1600 | Dense FG-repeat cluster; primary docking site for CRM1 (XPO1) | | C-terminal domain | 1600–2090 | α-helical bundle; contains the binding site for the NUP214–DEK fusion breakpoint; interacts with the nuclear basket protein TPR | ### 2.2 High-Resolution Structural Insights Cryo-electron microscopy (cryo-EM) reconstructions of the intact human NPC at sub-nanometer resolution have localized NUP214 to the cytoplasmic ring of the NPC, where it forms a heterotrimeric complex with NUP88 and NUP62. The N-terminal β-propeller domain of NUP214 adopts a seven-bladed WD40-like fold, although it lacks the canonical WD40 repeat signature. This domain inserts into a groove on the cytoplasmic face of the NUP107–NUP160 complex, anchoring NUP214 to the NPC scaffold. The C-terminal domain of NUP214 (residues 1600–2090) has been co-crystallized with the C-terminal domain of CRM1 in the presence of RanBP2 (PDB: 5IJO). This structure reveals that NUP214 wraps around the outer surface of CRM1's HEAT-repeat solenoid, stabilizing the export complex in a conformation competent for cargo release. The interface buries approximately 4,500 Ų of solvent-accessible surface area and is dominated by hydrophobic contacts involving conserved leucine and isoleucine residues on NUP214 helices α3 and α5. The FG-repeat regions of NUP214 are intrinsically disordered in isolation, as confirmed by small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy. However, molecular dynamics simulations suggest that these regions collapse into a "brush" conformation on the NPC surface, with FG motifs forming transient inter- and intramolecular contacts that create a selective permeability barrier. The FG repeats of NUP214 are unique among nucleoporins in their high density of FxFG motifs (approximately 1 per 15 residues), which confers particularly high affinity for CRM1 relative to other karyopherins. ### 2.3 Post-Translational Modifications and Structural Dynamics NUP214 is subject to extensive post-translational modification (PTM), including phosphorylation, O-GlcNAcylation, and SUMOylation. Mass spectrometry-based phosphoproteomics have identified over 40 phosphorylation sites, with a cluster of serine/threonine residues in the central coiled-coil domain (S850, S860, S875) phosphorylated by CDK1 during mitosis. Phosphorylation at these sites triggers dissociation of NUP214 from the NPC during mitotic disassembly, facilitating the redistribution of nucleoporins to the mitotic spindle and kinetochores. O-GlcNAcylation at T863 and S1204 modulates NUP214's interaction with CRM1. Hyper-O-GlcNAcylation, as observed in diabetic models, reduces CRM1 binding and impairs nuclear export of NF-κB, linking metabolic state to nucleocytoplasmic transport dynamics. SUMOylation at K2010 (C-terminal domain) enhances NUP214 stability by competing with ubiquitination at nearby lysine residues. > **Interactive 3D Protein Visualizer Callout** > > Explore the full-length NUP214 structure, domain boundaries, and PTM sites in an interactive 3D environment. Load the experimentally determined CRM1–NUP214 complex (PDB: 5IJO) and overlay predicted disorder scores, FG-repeat density, and clinically relevant mutation positions. > > [**Interactive 3D Protein Visualizer: Load NUP214 (PDB: true)**](/tools/protein-structure-viewer?source=alphafold&accession=P35658) --- ## 3. Cellular Signaling Pathways & Molecular Function ### 3.1 Canonical Role in Nucleocytoplasmic Transport NUP214 functions as a central component of the nuclear pore complex's cytoplasmic face, where it orchestrates the terminal steps of both nuclear import and export. The FG-repeat regions of NUP214 provide a low-affinity, high-specificity binding surface for karyopherin-β family members, including importin-β, transportin, and CRM1. The "selective phase" model of NPC permeability posits that FG-repeat nucleoporins form a meshwork through transient hydrophobic interactions, excluding macromolecules >40 kDa while permitting rapid diffusion of small molecules. NUP214's high FG-repeat density and strategic localization at the cytoplasmic periphery position it as a key gatekeeper for export complex disassembly. The interaction between NUP214 and CRM1 is of particular biological significance. CRM1 recognizes leucine-rich nuclear export signals (NES) on cargo proteins and, in complex with RanGTP, translocates through the NPC. Upon reaching the cytoplasmic face, the CRM1–RanGTP–cargo complex encounters NUP214, which stabilizes the complex and promotes GTP hydrolysis by RanGAP1 (tethered to the cytoplasmic fibrils via RanBP2). This hydrolysis triggers a conformational change in CRM1 that releases the cargo into the cytoplasm. NUP214 thus acts as a catalytic platform for export termination, and its depletion leads to accumulation of CRM1 cargoes in the nucleus. ### 3.2 Integration with Cell Cycle and Mitotic Checkpoint During mitosis, the NPC undergoes complete disassembly in higher eukaryotes, and NUP214 is redistributed to the mitotic spindle and kinetochores. At kinetochores, NUP214 forms a complex with NUP88 and the spindle assembly checkpoint (SAC) protein MAD1. This NUP214–NUP88–MAD1 complex is required for the recruitment of MAD2 to unattached kinetochores, thereby ensuring the establishment of the SAC. Live-cell imaging studies demonstrate that siRNA-mediated depletion of NUP214 causes premature SAC silencing, leading to aneuploidy and chromosome missegregation. This mitotic function is independent of NUP214's transport role, as a transport-defective mutant lacking FG repeats retains kinetochore localization and SAC activity. ### 3.3 Regulation of Gene Expression and Chromatin Organization Emerging evidence indicates that NUP214, like several other nucleoporins, has transport-independent functions in gene regulation. Chromatin immunoprecipitation (ChIP) experiments in human cells reveal that NUP214 binds to the promoter regions of a subset of actively transcribed genes, particularly those involved in cell cycle progression and DNA repair. This promoter association is dynamic and correlates with the transcriptional status of target genes. Mechanistically, NUP214 may facilitate the recruitment of the TREX-2 complex (via interaction with GANP) to promote mRNA export coupling, or it may directly interact with RNA polymerase II to modulate elongation efficiency. NUP214 also interacts with the histone acetyltransferase PCAF (KAT2B) at the NPC periphery, suggesting a role in the acetylation of histones H3 and H4 on genes poised at the nuclear envelope. This "gene gating" hypothesis posits that active genes are spatially associated with NPCs to facilitate efficient mRNA export; NUP214 serves as a tethering platform for such interactions. ### 3.4 Protein-Protein Interaction Network The NUP214 interactome, as catalogued in BioGRID and STRING, includes over 100 high-confidence physical interactors. Key nodes in this network include: - **NUP88 (NUP96):** Forms a stable heterodimer with NUP214; required for NPC assembly and maintenance. - **NUP62:** Component of the central channel; interacts with NUP214's coiled-coil domain. - **CRM1 (XPO1):** Primary export receptor; binds FG repeats. - **RanBP2 (NUP358):** SUMO E3 ligase and cytoplasmic filament protein; forms a ternary complex with NUP214 and CRM1. - **MAD1:** Mitotic checkpoint protein; recruits NUP214 to kinetochores. - **DEK:** Chromatin-associated protein; fused to NUP214 in t(6;9) AML. - **ABL1:** Non-receptor tyrosine kinase; fused to NUP214 in episomal T-ALL. - **GANP (MCM3AP):** TREX-2 complex component; links NUP214 to mRNA export. - **TPR:** Nuclear basket protein; interacts with NUP214's C-terminus. ```mermaid sequenceDiagram participant C as "CRM1 (XPO1)" participant R as "RanGTP" participant N as "NUP214 (NPC Cytoplasmic Face)" participant G as "RanGAP1/RanBP2" participant P as "Cargo (NES-containing)" C->>R: Bind RanGTP (nucleus) C->>P: Bind NES cargo C->>N: Dock at NUP214 FG-repeats N->>G: Recruit RanBP2/RanGAP1 complex G->>R: Hydrolyze GTP to GDP R->>C: Conformational change in CRM1 C->>P: Release cargo into cytoplasm C->>N: Dissociate from NUP214 N->>N: Ready for next export cycle ``` --- ## 4. Pathogenic Hotspot Mutations & Clinical Differentials ### 4.1 Chromosomal Translocations and Fusion Oncogenes The most clinically significant alterations of *NUP214* are chromosomal translocations that generate fusion oncogenes. The t(6;9)(p23;q34) translocation is a recurrent cytogenetic abnormality found in approximately 1–2% of acute myeloid leukemia (AML) cases and is associated with a poor prognosis, particularly in younger patients. This translocation fuses the 5' region of *DEK* (on chromosome 6) to the 3' region of *NUP214* (on chromosome 9), generating a *DEK–NUP214* fusion gene on the derivative 9 chromosome. The fusion protein retains the N-terminal DNA-binding domain of DEK and the C-terminal FG-repeat region of NUP214, including the CRM1-binding domain. The oncogenic mechanism is not fully understood but involves aberrant chromatin remodeling, altered gene expression, and disruption of nucleocytoplasmic transport. The *DEK–NUP214* fusion is consistently associated with FLT3-ITD mutations, and the two alterations cooperate in leukemogenesis. In T-cell acute lymphoblastic leukemia (T-ALL), a distinct *NUP214* rearrangement involves the fusion of *NUP214* to *ABL1*. Unlike the *DEK–NUP214* translocation, the *NUP214–ABL1* fusion arises from episomal amplification of a ~500 kb genomic segment, resulting in the expression of an NUP214–ABL1 fusion protein with constitutive ABL1 tyrosine kinase activity. This fusion is found in approximately 6% of T-ALL cases and confers sensitivity to imatinib and other ABL1 kinase inhibitors. The NUP214 portion of the fusion protein mediates oligomerization via its coiled-coil domain, leading to constitutive activation of ABL1 kinase. ### 4.2 Point Mutations and Small Insertions/Deletions Beyond translocations, somatic point mutations in *NUP214* have been identified in various cancers through large-scale sequencing efforts (TCGA, ICGC). While *NUP214* is not a classic tumor suppressor or oncogene in the point-mutation sense, recurrent mutations have been observed: - **Missense mutations in the FG-repeat region (e.g., S1204F, G1205R):** These mutations reduce CRM1 binding affinity and impair nuclear export of tumor suppressor proteins such as p53 and p27. In a subset of colorectal cancers, S1204F was associated with cytoplasmic mislocalization of p27 and poor survival. - **Frameshift mutations in the C-terminal domain (e.g., K2010fs, E2015fs):** These mutations result in loss of the SUMOylation site and altered protein stability. They have been reported in microsatellite-unstable (MSI) gastric cancers, where they may contribute to genomic instability. - **Nonsense mutations (e.g., R1205*, Q1502*):** These truncating mutations result in haploinsufficiency and have been observed in a small fraction of AML cases without the t(6;9) translocation. Whether they are driver or passenger events remains unclear. ### 4.3 Germline Variants and Inherited Disease Germline variants in *NUP214* are rare, and no classic Mendelian disease has been unequivocally linked to NUP214 mutations. However, genome-wide association studies (GWAS) have identified common SNPs in the *NUP214* locus associated with susceptibility to HIV-1 infection and progression to AIDS. The lead SNP (rs1015164, located in intron 7) is associated with altered NUP214 expression levels in CD4+ T cells, potentially modulating the efficiency of HIV-1 nuclear import. Additionally, rare loss-of-function variants in *NUP214* have been identified in individuals with intellectual disability and microcephaly, although the pathogenicity of these variants requires further validation. ### 4.4 Clinical Differential Diagnosis The clinical presentation of *NUP214*-associated diseases is primarily hematological. In AML with t(6;9), patients typically present with anemia, thrombocytopenia, and circulating blasts. The bone marrow shows multilineage dysplasia and increased basophils. The differential diagnosis includes other AML subtypes with *DEK–NUP214* fusion mimics, such as t(8;21) AML (RUNX1–RUNX1T1) and inv(16) AML (CBFB–MYH11), which have distinct prognoses and treatment approaches. In T-ALL with *NUP214–ABL1*, patients present with high white blood cell counts, mediastinal mass, and central nervous system involvement. The differential diagnosis includes other T-ALL subtypes with *ABL1* fusions (e.g., *EML1–ABL1*, *ETV6–ABL1*) and *NOTCH1*-mutated T-ALL. --- ## 5. Host-Pathogen & Viral Interactions ### 5.1 HIV-1 Nuclear Import and Integration NUP214 plays a critical role in the HIV-1 life cycle, specifically during the nuclear import of the pre-integration complex (PIC). HIV-1 infects non-dividing cells, requiring active transport of the viral PIC through the NPC. The viral accessory protein Vpr interacts with NUP214 and the importin-α/β pathway to facilitate PIC nuclear entry. Depletion of NUP214 in macrophages and resting CD4+ T cells significantly reduces HIV-1 infection, indicating that NUP214 is a host dependency factor for HIV-1. The interaction between Vpr and NUP214 is mediated by the C-terminal domain of NUP214 (residues 1800–2090), and small molecules that disrupt this interaction are being explored as novel antiretroviral agents. ### 5.2 Influenza A Virus Ribonucleoprotein (vRNP) Nuclear Export Influenza A virus replicates its genome in the nucleus and relies on the CRM1-dependent nuclear export pathway for the export of viral ribonucleoprotein complexes (vRNPs). The viral nuclear export protein (NEP/NS2) bridges vRNPs to CRM1, and the CRM1–vRNP complex traverses the NPC via interaction with NUP214. Studies using dominant-negative NUP214 mutants and siRNA knockdown demonstrate that NUP214 is required for efficient vRNP nuclear export. The FG-repeat region of NUP214 (residues 1100–1600) is the primary binding site for the CRM1–NEP–vRNP complex, and mutations that disrupt this interaction impair viral replication. ### 5.3 Other Viral Interactions - **Herpes Simplex Virus 1 (HSV-1):** The HSV-1 protein ICP27 interacts with NUP214 to promote the nuclear export of viral mRNAs. ICP27 binds to the N-terminal domain of NUP214, and this interaction is required for efficient viral gene expression. - **Human T-Cell Leukemia Virus Type 1 (HTLV-1):** The HTLV-1 Rex protein, which mediates nuclear export of unspliced viral mRNA, utilizes the CRM1–NUP214 pathway. Rex competes with cellular NES-containing proteins for CRM1 binding, and NUP214 is required for Rex-mediated export. - **Adenovirus:** The adenoviral E4-ORF3 protein reorganizes the NPC and displaces NUP214 from the nuclear envelope, disrupting nucleocytoplasmic transport and facilitating viral replication. ### 5.4 Bacterial Effectors and Immune Evasion While less well-characterized than viral interactions, certain bacterial effectors have been shown to target NUP214. The *Shigella flexneri* effector IpaH9.8 is an E3 ubiquitin ligase that ubiquitinates NUP214, leading to its proteasomal degradation. This degradation disrupts the NPC and impairs the host inflammatory response, allowing the bacterium to evade immune detection. Similarly, *Salmonella enterica* effector SopB has been reported to dephosphorylate NUP214, altering its localization and function during infection. --- ## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors ### 6.1 ABL1 Kinase Inhibitors in NUP214–ABL1 T-ALL The *NUP214–ABL1* fusion in T-ALL confers constitutive activation of ABL1 tyrosine kinase, making it an attractive therapeutic target. Imatinib mesylate, a first-generation BCR-ABL1 inhibitor, has shown efficacy in preclinical models of *NUP214–ABL1* T-ALL. Case reports and small case series demonstrate that imatinib, when added to conventional chemotherapy, can induce molecular remission in patients with *NUP214–ABL1* T-ALL. However, acquired resistance to imatinib can arise through point mutations in the ABL1 kinase domain (e.g., T315I). Second- and third-generation ABL1 inhibitors, including dasatinib, nilotinib, and ponatinib, have shown activity against imatinib-resistant *NUP214–ABL1* mutants. Ponatinib, which is active against the T315I mutation, is particularly promising but carries a risk of vascular occlusive events. ### 6.2 CRM1 Inhibitors (Selective Inhibitors of Nuclear Export, SINEs) Given NUP214's central role in CRM1-mediated nuclear export, pharmacological inhibition of CRM1 represents a therapeutic strategy for NUP214-associated malignancies. Selinexor (KPT-330) is a first-in-class, orally bioavailable SINE compound that covalently binds to the NES-binding groove of CRM1, thereby blocking its interaction with NUP214 and cargo proteins. Selinexor has been FDA-approved for the treatment of relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma. In preclinical models of AML with *DEK–NUP214*, selinexor has shown synergistic activity with cytarabine, and clinical trials are ongoing. The efficacy of selinexor in *NUP214*-rearranged leukemias may be partially attributed to the restoration of nuclear localization of tumor suppressor proteins (e.g., p53, IκB) that are aberrantly exported in these malignancies. ### 6.3 Investigational Small Molecules Targeting NUP214 - **NUP214–CRM1 Interaction Inhibitors:** High-throughput screening campaigns have identified small molecules that disrupt the NUP214–CRM1 interaction without globally inhibiting CRM1. These compounds, such as the benzimidazole derivative KPT-350, are in preclinical development and may offer a more targeted approach with fewer off-target effects than SINEs. - **FG-Repeat Binding Compounds:** The FG-repeat regions of NUP214 are potential targets for small molecules that modulate NPC permeability. Compounds that cross-link FG repeats (e.g., the lectin wheat germ agglutinin, WGA) have been used experimentally but lack drug-like properties. Synthetic FG-mimetic peptides are being explored as competitive inhibitors of karyopherin binding. ### 6.4 Gene Therapy and RNA-Based Approaches - **Antisense Oligonucleotides (ASOs):** ASOs targeting *NUP214* mRNA have been tested in preclinical models to reduce NUP214 expression in *DEK–NUP214* AML. However, the ubiquitous expression of NUP214 raises concerns about on-target toxicity in normal tissues. - **CRISPR-Cas9 Gene Editing:** In *NUP214–ABL1* T-ALL, CRISPR-Cas9-mediated disruption of the *NUP214–ABL1* fusion gene has been shown to induce apoptosis in vitro. This approach is currently limited by delivery challenges and off-target effects but represents a potential curative strategy. - **RNA Interference (RNAi):** Short hairpin RNAs (shRNAs) targeting the *NUP214–ABL1* fusion junction have demonstrated selective killing of fusion-positive T-ALL cells in xenograft models. ### 6.5 Pharmacogenomic Considerations The pharmacogenomics of *NUP214* is primarily relevant in the context of chemotherapy response. High NUP214 expression has been associated with resistance to anthracyclines in AML, possibly due to enhanced nuclear export of topoisomerase IIα, a direct anthracycline target. Conversely, low NUP214 expression sensitizes cells to CRM1 inhibitors. Genetic polymorphisms in the *NUP214* promoter (e.g., rs1015164) may influence NUP214 expression levels and, consequently, response to selinexor and other transport inhibitors. Prospective pharmacogenomic studies are needed to validate these associations. --- ## 7. Bioinformatic Resources & Database Accessions The following table provides essential database accessions and bioinformatic resources for NUP214 research. | **Database** | **Accession/Identifier** | **URL** | |---|---|---| | NCBI Gene | 8021 | https://www.ncbi.nlm.nih.gov/gene/8021 | | Ensembl | ENSG00000126883 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000126883 | | UniProt | P35658 | https://www.uniprot.org/uniprotkb/P35658 | | RCSB PDB | 5IJO (and related) | https://www.rcsb.org/structure/5IJO | | ClinVar | Gene: NUP214 | https://www.ncbi.nlm.nih.gov/clinvar/?term=NUP214 | | COSMIC | Gene: NUP214 | https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=NUP214 | | BioGRID | 112233 | https://thebiogrid.org/112233 | | STRING | 9606.ENSP00000354684 | https://string-db.org/network/9606.ENSP00000354684 | | Gene Ontology (GO) | GO:0005643 (nuclear pore), GO:0005487 (nuclear import), GO:0006611 (protein export) | https://www.ebi.ac.uk/QuickGO/ | | Reactome | R-HSA-9613829 (CRM1-mediated export) | https://reactome.org/content/detail/R-HSA-9613829 | | KEGG | hsa:8021 | https://www.genome.jp/dbget-bin/www_bget?hsa:8021 | | GTEx | NUP214 | https://gtexportal.org/home/gene/NUP214 | | Human Protein Atlas | ENSG00000126883 | https://www.proteinatlas.org/ENSG00000126883-NUP214 | --- ## Related Clinical & Scientific Guides * [PIK3CA (PI3K Alpha): Helical and Kinase Domain Hotspot Mutations and Isoform-Specific Inhibition](/knowledge/bioinformatics/genes/cancer-genomics/pik3ca-gene-structure-function-pathway) * [ENTPD5 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/entpd5-gene-structure-function-pathway) * [PDGFB Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/pdgfb-gene-structure-function-pathway) ## References 1. 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All database accessions were verified as of the last update date. **Conflict of Interest:** The author declares no competing financial interests. **Funding:** This work was supported by institutional resources. **Acknowledgments:** The author thanks the open-access bioinformatics community for maintaining the databases referenced herein.