Affinage

NSD3

Histone-lysine N-methyltransferase NSD3 · UniProt Q9BZ95

Length
1437 aa
Mass
161.6 kDa
Annotated
2026-06-10
80 papers in source corpus 28 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NSD3 (WHSC1L1) is a multidomain SET-domain histone methyltransferase that deposits H3K36 mono/dimethylation specifically at active promoters and enhancers, distinguishing it from the broad intergenic H3K36me2 patterns laid down by NSD1 and NSD2 (PMID:11374904, PMID:11549311, PMID:39390582). Its catalytic activity drives transcription of cell-cycle genes such as CDC6 and CDK2, and enzyme-dead mutants fail to rescue the proliferation defects of NSD3-depleted cells, establishing a direct catalytic requirement for cell-cycle progression (PMID:23011637, PMID:27285764). NSD3 also acts as a developmental regulator, supplying H3K36me2 required for neural crest specification gene expression (PMID:25318671). Histone-tail engagement is structurally encoded: an integrated PHD5-C5HCH module reads unmodified H3K4 and H3K9me3, while a PWWP1 methyl-lysine reader module is essential for cancer-cell viability and serves as a druggable pocket targeted by the BI-9321 chemical probe and the MS9715 PROTAC degrader, both of which suppress NSD3- and cMyc-driven transcriptional programs (PMID:23269674, PMID:31285596, PMID:34469831). NSD3 is expressed as a catalytically active long isoform and a short isoform (NSD3S) lacking the SET domain that functions as a chromatin adaptor: NSD3S bridges BRD4 — through a defined amphipathic motif that forms an antiparallel β-sheet on the BRD4 ET-domain three-helix bundle — to the CHD8 remodeler, and this adaptor function sustains acute myeloid leukemia and the differentiation block of NUT midline carcinoma (PMID:21555454, PMID:26626481, PMID:27291650, PMID:24875858). Beyond chromatin, NSD3 methylates non-histone substrates, monomethylating EGFR at K721 to potentiate oncogenic ERK signaling and IRF3 at K366 to enhance type I interferon production by displacing PP1cc and maintaining IRF3 phosphorylation (PMID:28102297, PMID:29101251). The long isoform additionally promotes mitotic sister-chromatid cohesion by recruiting the kollerin (NIPBL-MAU2) cohesin loader at mitotic exit, while NSD3S protects stalled replication forks in an ATR-dependent manner by antagonizing MRE11 recruitment, conferring PARP-inhibitor resistance (PMID:37288770, PMID:40578344). NSD3 is recurrently amplified and mutated in epithelial cancers, and a catalytically hyperactive variant (T1232A) accelerates lung squamous cell carcinoma, defining NSD3 as an oncogenic methyltransferase whose tumors are hypersensitive to bromodomain inhibition (PMID:11374904, PMID:11549311, PMID:33536620).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 Medium

    Establishing the domain architecture and genomic location framed NSD3 as a candidate chromatin-modifying enzyme amplified in cancer.

    Evidence Genomic cloning, domain analysis, and FISH mapping to 8p12 in breast cancer cell lines

    PMID:11374904 PMID:11549311

    Open questions at the time
    • No catalytic activity reconstituted
    • Substrate specificity unknown at this stage
  2. 2006 Medium

    First functional dissection assigned methyltransferase activity to the SET domain and a regulatory role to the PWWP region, though the histone substrate assignment differs from later consensus.

    Evidence Deletion mapping, point mutagenesis (C297), in vitro HMTase and caspase-3 assays

    PMID:17239852

    Open questions at the time
    • Reported H3K4/H3K27 substrate not concordant with later H3K36 consensus
    • Single-lab in vitro context
  3. 2011 High

    Identifying the BRD4 ET-domain interaction explained how NSD3 is targeted to active genes and coupled to pTEFb-independent transcription.

    Evidence Co-IP, ChIP recruitment, siRNA knockdown, reporter assay, H3K36 methylation readout

    PMID:21555454

    Open questions at the time
    • Did not resolve which isoform mediates the interaction
    • Structural basis not yet defined
  4. 2012 High

    Crystallography of the PHD5-C5HCH module and cell-cycle knockdown studies defined how NSD3 reads histone tails and linked its loss to mitotic defects.

    Evidence Crystal structures with H3 peptides plus ITC/NMR binding; siRNA with FACS cell-cycle analysis and expression profiling

    PMID:23011637 PMID:23269674

    Open questions at the time
    • Functional consequence of H3K9me3 recognition in vivo unresolved
    • Connection between reader binding and catalysis not established
  5. 2014 Medium

    Loss-of-function in neural crest and the discovery of the NSD3-NUT fusion oncoprotein established NSD3 in both normal development and oncogenic gene-regulatory programs through BRD4.

    Evidence Morpholino/dominant-negative with H3K36me2 ChIP in embryo; patient cell lines, shRNA, rescue, Co-IP, BET inhibitor in NUT carcinoma

    PMID:24875858 PMID:25318671

    Open questions at the time
    • Direct catalytic versus scaffold contribution to NUT carcinoma not separated at this point
    • In vivo developmental substrate scope incomplete
  6. 2015 High

    Isoform dissection revealed that the catalytically inactive short isoform, not the methyltransferase, is the adaptor coupling BRD4 to CHD8 at super-enhancers, redefining NSD3's role in AML.

    Evidence CRISPR/shRNA, domain truncation, Co-IP, BRD4/NSD3/CHD8 ChIP-seq co-localization, RNA-seq, BET inhibition

    PMID:26626481

    Open questions at the time
    • Mechanism of CHD8 engagement structurally undefined here
    • Whether catalytic isoform contributes independently unresolved
  7. 2016 High

    Structural and functional work converged to define the BRD4-ET–NSD3 amphipathic interface and to nail down a strict catalytic requirement for cell-cycle gene transcription and ERα chromatin binding.

    Evidence Crystal structure of ET–NSD3 peptide complex; catalytic-mutant rescue ChIP at CDC6/CDK2; ChIP-seq of ERα in breast cancer

    PMID:27005559 PMID:27285764 PMID:27291650

    Open questions at the time
    • How catalytic and scaffold functions are partitioned between isoforms in the same cell remains unclear
    • ERα regulatory mechanism downstream of NSD3 undefined
  8. 2017 High

    Identification of EGFR-K721 and IRF3-K366 as direct substrates extended NSD3 beyond histones into oncogenic signaling and antiviral immunity.

    Evidence In vitro methylation with MS site mapping, domain mapping, Co-IP, mutagenesis, interferon assays, in vivo NSD3 knockout

    PMID:28102297 PMID:29101251

    Open questions at the time
    • Full non-histone substrate repertoire unknown
    • In vivo stoichiometry and dynamics of these methylations not quantified
  9. 2018 Low

    An NSD3S–MYC interaction was reported, hinting at a direct link to the Myc oncogenic program.

    Evidence Cell lysate TR-FRET assay between Flag-NSD3 and GST-MYC

    PMID:29634317

    Open questions at the time
    • Indirect lysate-based detection without reciprocal Co-IP validation
    • No structural or cellular confirmation of the interaction
  10. 2019 High

    Chemical-probe and PROTAC development validated the PWWP1 methyl-lysine pocket as a tractable target whose engagement downregulates Myc and impairs leukemia growth.

    Evidence Fragment-based discovery with NMR/X-ray of probe-PWWP1 complex, cellular target engagement, qRT-PCR, proliferation; colorectal overexpression studies

    PMID:31190890 PMID:31285596

    Open questions at the time
    • Mechanistic link between PWWP1 occupancy and Myc transcription incompletely defined
    • Colorectal ERK/CAPG axis (Low confidence) lacks direct biochemical demonstration
  11. 2020 Medium

    Isoform-specific work showed the long catalytic isoform cooperates with EZH2 and Pol II to drive NOTCH-dependent EMT and metastasis, distinguishing catalytic from adaptor functions.

    Evidence Isoform knockdown/overexpression, H3K36me2/3 and Pol II ChIP, NSD3-EZH2 Co-IP, NOTCH reporter, in vivo tumor model

    PMID:32967925

    Open questions at the time
    • Direct NSD3-EZH2 structural interface not defined
    • Single-lab context
  12. 2021 High

    Comprehensive in vivo and structural work established NSD3 as a bona fide H3K36me2 oncogenic driver in LUSC and showed a hyperactive variant relieves auto-inhibition to accelerate tumorigenesis.

    Evidence In vitro methylation, MD simulations, mouse KO/knock-in LUSC models, PDX, CRISPR, ChIP, BET inhibition; PROTAC MS9715 degradation with KO comparison

    PMID:33536620 PMID:34469831

    Open questions at the time
    • Endogenous regulators of the auto-inhibitory conformation in normal cells unknown
    • Relationship between catalytic LUSC driving and BET-inhibitor sensitivity mechanistically incomplete
  13. 2023 Medium

    NSD3 was assigned a mitotic role, with the long isoform recruiting the kollerin cohesin loader and requiring catalytic activity for sister-chromatid cohesion.

    Evidence Co-IP with NIPBL/MAU2, ChIP of NSD3/MAU2/RAD21, cohesion assays, isoform- and methyltransferase-dead rescue

    PMID:37288770

    Open questions at the time
    • Methyl substrate underlying cohesion promotion not identified
    • Single-lab finding awaiting independent confirmation
  14. 2024 High

    Multiple studies refined NSD3's genomic targeting specificity, identified additional non-epigenetic and regulatory functions, and defined how NSD3 itself is post-translationally stabilized.

    Evidence Systematic multi-KO ChIP-seq in mesenchymal stem cells; NSD3-PPP1CB-pSTAT3 trimer Co-IP and glycolysis assays; EHMT2-NSD3 Co-IP with K477 methylation MS and stability assays

    PMID:39119928 PMID:39390582 PMID:39741006

    Open questions at the time
    • Mechanism directing NSD3 specifically to active promoters/enhancers undefined
    • Generality of the STAT3 trimer function beyond lung adenocarcinoma unknown
  15. 2025 High

    New work defined isoform-segregated functions in genome stability and rDNA transcription, with NSD3S protecting stalled forks (PARPi resistance) and NSD3L driving Pol I transcription in the nucleolus.

    Evidence Co-IP, PLA, iPOND fork protection, PROTAC, PDX and PARPi assays; nucleolar MS, rDNA ChIP of Pol I/UBTF/FOSL2/H4K20me3, NSD3L ablation

    PMID:40578344 PMID:42082455

    Open questions at the time
    • Whether fork protection requires catalytic activity unresolved
    • Direct methyl substrate at the rDNA locus not identified
  16. 2026 Medium

    Chromosome-folding analyses linked NSD3 isoforms to 3D genome organization, stabilizing BRD4-NUT condensates and mediating long-range chromatin contacts.

    Evidence Hi-C, ChIP-seq, CRISPR KO, PWWP domain mutants, condensate imaging (preprint)

    PMID:41727024

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Mechanism by which catalytically inactive NSD3S drives megabase-scale contacts undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NSD3 isoform choice, catalytic versus scaffold activities, genomic targeting, and its expanding non-histone substrate set are integrated into a single regulatory logic across normal and malignant cells remains unresolved.
  • No unifying model linking targeting specificity to substrate selection
  • Endogenous control of long-versus-short isoform ratio incompletely defined
  • Complete non-histone methylome unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0140110 transcription regulator activity 2 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005730 nucleolus 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 2 R-HSA-4839726 Chromatin organization 2 R-HSA-168256 Immune System 1 R-HSA-73894 DNA Repair 1
Partners
BRD4CHD8EHMT2EZH2MAU2NIPBLPPP1CBPTIP
Complex memberships
kollerin (NIPBL-MAU2)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 NSD3 (WHSC1L1) encodes a SET domain-containing protein with two PWWP domains, five PHD zinc finger motifs, a SAC domain, and a SET domain, and maps to chromosome 8p12; it is amplified in breast cancer cell lines. Genomic cloning, domain analysis, FISH/chromosomal mapping Genomics Medium 11374904 11549311
2006 NSD3/WHISTLE methylates histone H3-K4 and H3-K27 to repress transcription, induces apoptosis via caspase-3 activation dependent on its HMTase activity, and recruits HDAC1 through its N-terminal PWWP region. The SET domain cysteine 297 is critical for HMTase activity, and the PWWP domain is required for HMTase activity by interacting with associating factors. Deletion mapping, point mutagenesis, in vitro HMTase assay, caspase-3 activation assay, reporter assay Experimental cell research Medium 17239852
2010 NSD3/WHISTLE interacts with heat shock protein HSP90α and the histone demethylase JMJD1C in a complex (identified by immunoaffinity TAP analysis). WHISTLE is recruited to the p450c17 promoter via SF-1 and represses transcription at prepubertal stages; JMJD1C then replaces WHISTLE to activate target gene expression during mouse testis development. Immunoaffinity TAP purification, ChIP, reporter assays, RT-PCR Nucleic acids research Medium 20530532
2011 NSD3 interacts with the extraterminal (ET) domain of BRD4 (and BRD2/BRD3); this interaction is required for pTEFb-independent transcriptional activation. NSD3 is recruited to BRD4 target genes in a BRD4-dependent manner and depletion of BRD4 or NSD3 reduces H3K36 methylation at target genes. Proteomic pulldown/Co-IP, ChIP, siRNA knockdown, transcriptional reporter assay Molecular and cellular biology High 21555454
2012 The PHD5-C5HCH module of NSD3 forms a novel integrated PHD-PHD-like structural module that binds histone H3 N-terminal peptides, recognizing unmodified H3K4 and trimethylated H3K9 (H3K9me3) via PHD5. This binding specificity differs from NSD1 (which does not bind H3 peptides) and NSD2 (which prefers H3K9me0 over H3K9me3). Crystal structure determination (apo and H3 peptide-bound states), binding assays (ITC/NMR) The Journal of biological chemistry High 23269674
2012 WHSC1L1/NSD3 knockdown causes G2/M cell cycle arrest followed by multinucleation in bladder and lung cancer cell lines, and H3K36 dimethylation (H3K36me2) is reduced; downstream transcriptional targets include CCNG1 and NEK7. siRNA knockdown, cell cycle analysis (FACS), gene expression profiling (Affymetrix GeneChip) Genes, chromosomes & cancer Medium 23011637
2014 NSD3 is required for neural crest specification: it is expressed in premigratory and migratory neural crest cells, and is necessary for expression of neural plate border gene Msx1 and neural crest transcription factors Sox10, Snail2, Sox9, and FoxD3. H3K36me2 at the Sox10 locus specifically requires NSD3. A separate, direct requirement for NSD3-related methyltransferase activity exists during neural crest migration (shown by dominant-negative approach restricted to migratory stages). In situ hybridization, morpholino knockdown, dominant-negative expression (temporal restriction), ChIP for H3K36me2 Molecular biology of the cell Medium 25318671
2014 NSD3-NUT fusion oncoprotein is both necessary and sufficient for blockade of differentiation and maintenance of proliferation in NUT midline carcinoma (NMC) cells. NSD3-NUT binds to BRD4, and BRD4 bromodomain inhibitors reverse its oncogenic effects. NSD3 itself is required for the differentiation block in BRD4-NUT-expressing NMC cells. Patient-derived cell line establishment, shRNA knockdown, rescue experiments, Co-IP (NSD3-NUT:BRD4 interaction), BET bromodomain inhibitor treatment with differentiation assay Cancer discovery High 24875858
2015 AML maintenance by BRD4 requires its interaction with the short isoform of NSD3 (NSD3-short), which lacks the methyltransferase domain. NSD3-short acts as an adaptor linking BRD4 (via BRD4 ET domain) to the CHD8 chromatin remodeler, using a PWWP chromatin reader module and an acidic transactivation domain. BRD4, NSD3, and CHD8 co-localize at super-enhancers across the AML genome and are co-released upon BET inhibition. CRISPR/Cas9 and shRNA knockdown (NSD3, CHD8), domain truncation analysis, Co-IP, ChIP-seq (BRD4/NSD3/CHD8 co-localization), RNA-seq, BET inhibitor treatment Molecular cell High 26626481
2016 The ET domain of BRD4 recognizes an amphipathic sequence motif of NSD3 by establishing a two-strand antiparallel β-sheet anchored on a hydrophobic cleft of the ET domain three-helix bundle. This structural mechanism is required for BRD4-NSD3 interaction essential for AML maintenance. Crystal structure of BRD4 ET domain–NSD3 peptide complex, mutational analysis Structure High 27291650
2016 WHSC1L1/NSD3 enrichment and H3K36me2 at gene bodies of CDC6 and CDK2 directly regulates their transcription; WHSC1L1 knockdown causes G0/G1 arrest rescuable by wild-type but not enzyme-inactive WHSC1L1, demonstrating a requirement for catalytic activity in cell cycle progression. ChIP (WHSC1L1, H3K36me2), siRNA knockdown, rescue with wild-type vs. catalytic mutant, FACS cell cycle analysis Oncotarget Medium 27285764
2016 WHSC1L1/NSD3 short isoform knockdown dramatically reduces ESR1 mRNA and ERα protein levels in SUM-44 breast cancer cells; loss of WHSC1L1 abrogates estrogen-independent ERα binding to chromatin (assessed by ChIP-Seq), which is restored by estradiol. siRNA/shRNA knockdown, ChIP-Seq, Western blot, RT-qPCR Molecular oncology Medium 27005559
2017 NSD3/WHSC1L1 directly mono-methylates lysine 721 in the tyrosine kinase domain of EGFR; this methylation enhances ERK cascade activation without EGF and increases nuclear EGFR interaction with PCNA, promoting DNA synthesis and cell cycle progression in head and neck squamous cell carcinoma. In vitro methylation assay (mass spectrometry identification of K721me1), Co-IP (EGFR-PCNA), siRNA knockdown, cell cycle/DNA synthesis assays Scientific reports Medium 28102297
2017 NSD3 directly methylates IRF3 at K366 (monomethylation) via its SET domain; NSD3 binds the IRF3 C-terminal region through its PWWP1 domain (identified by mass spectrometry of IRF3-associated proteins). K366 monomethylation enhances IRF3 transcriptional activity by promoting IRF3 dissociation from protein phosphatase PP1cc, thereby maintaining IRF3 phosphorylation and type I interferon production. NSD3 deficiency impairs antiviral innate immune response in vivo. Mass spectrometry of IRF3-associated proteins, in vitro methylation assay (NSD3 SET domain), domain mapping (PWWP1 binding), Co-IP (NSD3-IRF3, IRF3-PP1cc), site-directed mutagenesis (K366), interferon production assay, in vivo NSD3 knockout The Journal of experimental medicine High 29101251
2018 NSD3-short (NSD3S) interacts with MYC (c-Myc), as detected by cell lysate-based TR-FRET assay, identifying a protein-protein interaction relevant to NSD3S oncogenic activity. TR-FRET assay (Flag-NSD3, GST-MYC in HEK293T lysates), orthogonal protein-protein interaction assay Assay and drug development technologies Low 29634317
2019 The PWWP1 domain of NSD3 is required for cancer cell viability; BI-9321, a fragment-based chemical probe, targets the methyl-lysine binding site of NSD3-PWWP1 with sub-micromolar in vitro affinity, engages the target at 1 µM in cells, and downregulates Myc mRNA expression, reducing proliferation in MOLM-13 AML cells. Fragment-based drug discovery (NMR, X-ray crystallography of probe-PWWP1 complex), cellular target engagement assay, qRT-PCR (Myc expression), cell proliferation assay Nature chemical biology High 31285596
2019 NSD3 overexpression activates ERK1/2 signaling and enhances CAPG expression in colorectal cancer cells, promoting proliferation and migration; these effects are partially reversed by ERK1/2 inhibitor (PD98059) or CAPG siRNA. siRNA knockdown, overexpression, Western blot (ERK1/2 phosphorylation), cell proliferation and migration assays, pharmacological inhibition OncoTargets and therapy Low 31190890
2020 NSD3 long isoform (full-length, with catalytic domain), but not the short isoform lacking the catalytic domain, cooperates with EZH2 and RNA polymerase II to drive H3K36me2/3-dependent transactivation of genes associated with NOTCH receptor cleavage, leading to nuclear accumulation of NICD and NICD-mediated transcriptional repression of E-cadherin. This promotes breast cancer cell stemness, EMT, and metastasis. Isoform-specific knockdown/overexpression, ChIP (H3K36me2/3, RNA Pol II), Co-IP (NSD3-EZH2), NOTCH pathway reporter, NICD nuclear localization assay, E-cadherin promoter ChIP, in vivo mouse tumor model Cancer research Medium 32967925
2021 NSD3 is a catalytically active H3K36me2 methyltransferase and a key driver of lung squamous cell carcinoma (LUSC). An LUSC-associated variant NSD3(T1232A) shows increased catalytic activity for H3K36me2 in vitro and in vivo due to structural changes that relieve auto-inhibition. Expression of NSD3(T1232A) accelerates tumorigenesis in mouse models of LUSC. NSD3-dependent oncogenic activity requires its catalytic activity and promotes oncogenic gene expression via chromatin landscape reprogramming. NSD3-amplified/mutant LUSCs are hypersensitive to bromodomain inhibition. In vitro methylation assays, structural dynamic analysis (MD simulations), mouse LUSC models (KO and knock-in), patient-derived xenograft, CRISPR/Cas9, ChIP (H3K36me2), gene expression profiling, BET inhibitor treatment Nature High 33536620
2021 NSD3 PROTAC degrader MS9715 (linking BI-9321/PWWP1 antagonist to VHL E3 ligase ligand) achieves selective NSD3 degradation and suppresses both NSD3 and cMyc oncogenic transcriptional programs in hematological cancer cells, with superior efficacy over PWWP1 blockade alone. PROTAC degradation assay, Western blot, transcriptomic profiling (RNA-seq), CRISPR-Cas9 NSD3 KO comparison, cell growth assay Cell chemical biology Medium 34469831
2023 NSD3 is essential for mitotic sister chromatid cohesion: the long isoform interacts with the cohesin loader complex kollerin (NIPBL-MAU2) and promotes chromatin recruitment of MAU2 and cohesin at mitotic exit. NSD3 associates with chromatin in early anaphase prior to MAU2 and RAD21 recruitment, and its methyltransferase activity is required for efficient sister chromatid cohesion. Co-IP (NSD3-NIPBL/MAU2), ChIP (NSD3, MAU2, RAD21), siRNA knockdown with cohesion assay (sister chromatid separation), isoform-specific rescue, methyltransferase-dead mutant rescue Journal of cell science Medium 37288770
2024 NSD3 deposits H3K36me2 specifically at active promoters and enhancers (in contrast to NSD1/NSD2 which deposit H3K36me2 at broad intergenic regions). In the hierarchy of H3K36me1/2 deposition, NSD1 > NSD2 > NSD3 > ASH1L. Systematic genetic perturbations (single and combinatorial KO) in mouse mesenchymal stem cells, ChIP-seq (H3K36me1/2/3), comparative genomic analysis Genome biology High 39390582
2024 NSD3 forms a trimer with PPP1CB and p-STAT3 at the protein level (Co-IP), facilitating PPP1CB-mediated dephosphorylation of STAT3, which suppresses HK2 transcription and glycolysis in lung adenocarcinoma cells. This is a non-epigenetic function of NSD3. Co-IP (NSD3-PPP1CB-p-STAT3 trimer), Western blot (p-STAT3 levels), ChIP (HK2 promoter), glycolysis assay (glucose uptake, lactate production), siRNA knockdown Advanced science Medium 39119928
2024 EHMT2 interacts with and methylates NSD3 at lysine 477, stabilizing NSD3 protein levels in variant human embryonic stem cells; NSD3 protein levels are regulated by protein degradation in normal hESCs, and methylation-mediated stabilization drives oncogenic transformation. Co-IP (EHMT2-NSD3), mass spectrometry identification of K477 methylation, NSD3 knockdown rescue experiments, protein stability assay (cycloheximide chase), cell transformation assays Life science alliance Medium 39741006
2025 The short isoform of NSD3 (NSD3S, lacking methyltransferase domain) is upregulated by impaired CUL3-ZBTB2 E3 ubiquitin ligase-mediated degradation; ATR kinase drives localization of NSD3S to stalled replication forks where it antagonizes PTIP-dependent MRE11 nuclease recruitment, protecting nascent DNA from degradation and stabilizing stalled forks, thereby conferring PARP inhibitor resistance in prostate cancer. Co-IP (NSD3S-PTIP, NSD3S-MRE11), proximity ligation assay (NSD3S at replication forks), iPOND (isolation of proteins on nascent DNA), siRNA/shRNA knockdown, PROTAC degradation, cell-line and PDX xenograft models, PARP inhibitor sensitivity assays Molecular cell High 40578344
2025 NSD3 long isoform (NSD3L) localizes to the nucleolus, binds nucleolar proteins, and triggers ribosomal DNA (rDNA) transcription by promoting Polymerase I and UBTF binding to the rDNA locus, while displacing the transcriptional repressor FOSL2 from the rDNA upstream region. NSD3L also prevents deposition of repressive H4K20me3 by competing with SUV4-20H. Unbiased mass spectrometry (nucleolar protein binding), ChIP (Pol I, UBTF, FOSL2, H4K20me3 on rDNA), NSD3L knockout/ablation, nucleolar localization by imaging, rRNA expression assay Cell death & disease Medium 42082455
2026 NSD3 (via its long isoform) mediates chromosome folding in NUT carcinoma cells: it stabilizes the BRD4-NUT fusion oncoprotein on chromatin, promotes H3K36me2, and supports BRD4-NUT nuclear condensates; NSD3 loss attenuates distant chromatin interactions between BRD4-NUT megadomains. In fusion-negative cells, NSD3-short (catalytically inactive) promotes long-range chromatin contacts (>megabases) in a PWWP domain-dependent manner. Hi-C/chromatin conformation capture, ChIP-seq (H3K36me2, BRD4-NUT), CRISPR NSD3 knockout, domain-mutant NSD3 (PWWP mutant), live-cell imaging of condensates, fractionation bioRxivpreprint Medium 41727024

Source papers

Stage 0 corpus · 80 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Molecular and cellular biology 442 21555454
2014 NSD3-NUT fusion oncoprotein in NUT midline carcinoma: implications for a novel oncogenic mechanism. Cancer discovery 211 24875858
2019 WHISTLE: a high-accuracy map of the human N6-methyladenosine (m6A) epitranscriptome predicted using a machine learning approach. Nucleic acids research 178 30993345
2002 NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 153 11986249
2001 NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Genomics 139 11374904
2015 NSD3-Short Is an Adaptor Protein that Couples BRD4 to the CHD8 Chromatin Remodeler. Molecular cell 133 26626481
2021 Elevated NSD3 histone methylation activity drives squamous cell lung cancer. Nature 128 33536620
2019 Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3. Nature chemical biology 76 31285596
2010 Regulation of mouse steroidogenesis by WHISTLE and JMJD1C through histone methylation balance. Nucleic acids research 67 20530532
2007 Testicular cancer trends as 'whistle blowers' of testicular developmental problems in populations. International journal of andrology 66 17705804
2020 NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression. Cancer research 65 32967925
2016 Structural Mechanism of Transcriptional Regulator NSD3 Recognition by the ET Domain of BRD4. Structure (London, England : 1993) 64 27291650
2012 The histone methyltransferase Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1) is involved in human carcinogenesis. Genes, chromosomes & cancer 60 23011637
2012 The methyltransferase NSD3 has chromatin-binding motifs, PHD5-C5HCH, that are distinct from other NSD (nuclear receptor SET domain) family members in their histone H3 recognition. The Journal of biological chemistry 53 23269674
2017 The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3. The Journal of experimental medicine 51 29101251
2012 No one can whistle a symphony alone - how different ubiquitin linkages cooperate to orchestrate NF-κB activity. Journal of cell science 51 22389394
2001 WHSC1L1, on human chromosome 8p11.2, closely resembles WHSC1 and maps to a duplicated region shared with 4p16.3. Genomics 50 11549311
2021 A NSD3-targeted PROTAC suppresses NSD3 and cMyc oncogenic nodes in cancer cells. Cell chemical biology 47 34469831
2022 The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors. Cellular and molecular life sciences : CMLS 45 35532818
2009 NUP98-NSD3 fusion gene in radiation-associated myelodysplastic syndrome with t(8;11)(p11;p15) and expression pattern of NSD family genes. Cancer genetics and cytogenetics 45 19380029
2017 WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer. Scientific reports 43 28102297
2014 NSD3-NUT-expressing midline carcinoma of the lung: first characterization of primary cancer tissue. Pathology, research and practice 39 25466466
2016 Amplification of WHSC1L1 regulates expression and estrogen-independent activation of ERα in SUM-44 breast cancer cells and is associated with ERα over-expression in breast cancer. Molecular oncology 38 27005559
2016 WHSC1L1 drives cell cycle progression through transcriptional regulation of CDC6 and CDK2 in squamous cell carcinoma of the head and neck. Oncotarget 38 27285764
2013 PPAPDC1B and WHSC1L1 are common drivers of the 8p11-12 amplicon, not only in breast tumors but also in pancreatic adenocarcinomas and lung tumors. The American journal of pathology 34 24051013
2005 Evaluation of NSD2 and NSD3 in overgrowth syndromes. European journal of human genetics : EJHG 33 15483650
2015 Cytological Features of a Variant NUT Midline Carcinoma of the Lung Harboring the NSD3-NUT Fusion Gene: A Case Report and Literature Review. Case reports in pathology 32 25685583
2022 Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase. European journal of medicinal chemistry 31 35717870
2022 Thyroid Carcinoma with NSD3::NUTM1 Fusion: a Case with Thyrocyte Differentiation and Colloid Production. Endocrine pathology 28 34997561
2022 NUTM1 -rearranged Carcinoma of the Thyroid : A Distinct Subset of NUT Carcinoma Characterized by Frequent NSD3 - NUTM1 Fusions. The American journal of surgical pathology 25 36040068
2018 The role of histone lysine methyltransferase NSD3 in cancer. OncoTargets and therapy 25 30013365
2017 Amplification of the NSD3-BRD4-CHD8 pathway in pelvic high-grade serous carcinomas of tubo-ovarian and endometrial origin. Molecular and clinical oncology 25 28781807
2017 Silencing of histone methyltransferase NSD3 reduces cell viability in osteosarcoma with induction of apoptosis. Oncology reports 24 28901481
2014 Neural crest specification and migration independently require NSD3-related lysine methyltransferase activity. Molecular biology of the cell 22 25318671
2019 Downregulation of NSD3 (WHSC1L1) inhibits cell proliferation and migration via ERK1/2 deactivation and decreasing CAPG expression in colorectal cancer cells. OncoTargets and therapy 19 31190890
2017 Development of mammary hyperplasia, dysplasia, and invasive ductal carcinoma in transgenic mice expressing the 8p11 amplicon oncogene NSD3. Breast cancer research and treatment 18 28484924
2018 Development of a Time-Resolved Fluorescence Resonance Energy Transfer Ultrahigh-Throughput Screening Assay for Targeting the NSD3 and MYC Interaction. Assay and drug development technologies 16 29634317
2024 Systematic perturbations of SETD2, NSD1, NSD2, NSD3, and ASH1L reveal their distinct contributions to H3K36 methylation. Genome biology 15 39390582
2021 NSD3-NUTM1-rearranged carcinoma of the median neck/thyroid bed developing after recent thyroidectomy for sclerosing mucoepidermoid carcinoma with eosinophilia: report of an extraordinary case. Virchows Archiv : an international journal of pathology 14 33891143
2024 Histones Methyltransferase NSD3 Inhibits Lung Adenocarcinoma Glycolysis Through Interacting with PPP1CB to Decrease STAT3 Signaling Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 13 39119928
2023 NSD3: Advances in cancer therapeutic potential and inhibitors research. European journal of medicinal chemistry 13 37182335
2021 Structure, Activity and Function of the NSD3 Protein Lysine Methyltransferase. Life (Basel, Switzerland) 13 34440470
2006 The histone methyltransferase activity of WHISTLE is important for the induction of apoptosis and HDAC1-mediated transcriptional repression. Experimental cell research 13 17239852
2022 Dissecting the Immunological Profiles in NSD3-Amplified LUSC through Integrative Multi-Scale Analyses. Cancers 12 36291782
2021 WHISTLE server: A high-accuracy genomic coordinate-based machine learning platform for RNA modification prediction. Methods (San Diego, Calif.) 11 34245870
2016 The PWWP domain of the human oncogene WHSC1L1/NSD3 induces a metabolic shift toward fermentation. Oncotarget 11 28903324
2021 WHISTLE: A Functionally Annotated High-Accuracy Map of Human m6A Epitranscriptome. Methods in molecular biology (Clifton, N.J.) 9 33835461
2023 Identification of novel class inhibitors of NSD3 methyltransferase showing a unique, bivalent binding mode in the SET domain. Chemical biology & drug design 8 37072259
2021 High WHSC1L1 Expression Reduces Survival Rates in Operated Breast Cancer Patients with Decreased CD8+ T Cells: Machine Learning Approach. Journal of personalized medicine 8 34357103
2019 Protective effect of histone methyltransferase NSD3 on ISO-induced cardiac hypertrophy. FEBS letters 8 31254363
2024 NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions. International journal of molecular sciences 6 38256018
2010 A case of autologous microfat grafting in lip reconstruction of a whistle deformity following cancer treatment. The Canadian journal of plastic surgery = Journal canadien de chirurgie plastique 6 22131849
2023 Prospect of targeting lysine methyltransferase NSD3 for tumor therapy. Pharmacological research 5 37400043
2022 Rhabdomyosarcoma With Epithelioid Features And NSD3::FOXO1 Fusion: Evidence For Reconsideration Of Previously Reported FOXO1::FGFR1 Fusion. International journal of surgical pathology 5 35502835
2022 Possible Primary Thyroid Nuclear Protein in Testis Carcinomas with NSD3::NUTM1 Translocation Revealed by RNA Sequencing: A Report of Two Cases. Thyroid : official journal of the American Thyroid Association 5 35880417
2024 Targeted RNA sequencing in diagnostically challenging head and neck carcinomas identifies novel MON2::STAT6, NFATC2::NUTM2B, POC5::RAF1, and NSD3::NCOA2 gene fusions. Histopathology 4 39628352
2023 The histone methyltransferase NSD3 contributes to sister chromatid cohesion and to cohesin loading at mitotic exit. Journal of cell science 4 37288770
2023 WHSC1L1-mediated epigenetic downregulation of VMP1 participates in herpes simplex virus 1 infection-induced mitophagy impairment and neuroinflammation. Molecular immunology 4 37748280
2025 Isoform-specific function of NSD3 in DNA replication stress confers resistance to PARP inhibitors in prostate cancer. Molecular cell 3 40578344
2024 NSD3::NUTM1 Fusion Sarcoma Mimicking Malignant Peripheral Nerve Sheath Tumor with Prolonged Survival. Biomedicines 3 39200173
2023 Systematic perturbations of SETD2, NSD1, NSD2, NSD3 and ASH1L reveals their distinct contributions to H3K36 methylation. bioRxiv : the preprint server for biology 3 37905045
2019 High yield recombinant expression and purification of oncogenic NSD1, NSD2, and NSD3 with human influenza hemagglutinin tag. Protein expression and purification 3 31563542
2025 NSD3::FGFR1 : A Novel Gene Fusion First to Be Described in Merkel Cell Carcinoma. The American Journal of dermatopathology 2 40036479
2025 Acquisition of FGFR1 and NSD3 Amplifications During the Transformation of EGFR-Mutated Lung Adenocarcinoma into Squamous Cell Carcinoma: A Case Report. JTO clinical and research reports 2 40792216
2024 Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scattering. Frontiers in molecular biosciences 2 38516186
2022 Degradation of NSD3: What to Myc of it all? Cell chemical biology 2 35303440
2021 Histone Methyltransferase NSD3 Is a Lung Squamous Cell Carcinoma Driver. Cancer discovery 2 33579784
2014 Wetting the whistle: neurotropic factor improves salivary function. The Journal of clinical investigation 2 25036702
2025 NSD3: A Promising Target for Cancer Therapy. Cell biochemistry and function 1 40143436
2025 H3K36 histone methyltransferase NSD3 functions as a multifaceted regulator of late erythropoiesis. Biochemical and biophysical research communications 1 40532307
2025 The histone lysine methyltransferase NSD3 drives osteosarcomagenesis by inactivating ARID3A. Cancer letters 1 40967468
2026 NSD3 stabilizes nuclear compartmentalization and promotes megabase-scale chromatin interactions. bioRxiv : the preprint server for biology 0 41727024
2026 Fluorogenic Ligand Enables Identification of NSD3-Overexpressed Tumors by Targeting the PWWP1 Domain of NSD3. Analytical chemistry 0 41820229
2026 Histone methyltransferase G9a crosstalks with H3K36 histone methyltransferases NSD3 and SETD2 to mediate gene activation. Frontiers in cell and developmental biology 0 41970952
2026 The histone methyltransferase NSD3 oncogene triggers ribosomal DNA transcription, interfering with FOSL2 in cancer. Cell death & disease 0 42082455
2025 NSD3::NUTM1 fusion evidenced on RNA sequencing in poorly differentiated thyroid cancer: a report of two cases. European thyroid journal 0 40990092
2025 Histone methyltransferase NSD3 orchestrates early erythropoiesis by regulating erythroid progenitor cell differentiation and survival. Biochimica et biophysica acta. Molecular cell research 0 41360235
2024 Thyroid Carcinoma With NSD3::NUTM1 Fusion and Secondary TERT Promoter Mutation: A Case Report and Literature Review. International journal of surgical pathology 0 39285723
2024 NSD3 protein methylation and stabilization transforms human ES cells into variant state. Life science alliance 0 39741006
2018 [NSD3 suppresses LPS-triggered TNF-α production via promoting the dimethylation of histone H3K36 in macrophages]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 30236198

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