NSD2 (nuclear receptor binding SET domain protein 2 )

2012-05-01   Eva Martinez-Garcia , Jonathan D Licht 

Feinberg School of Medicine, Northwestern University, Hematology\\\/Oncology Division, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA

Identity

HGNC
LOCATION
4p16.3
LOCUSID
ALIAS
KMT3F,KMT3G,MMSET,REIIBP,TRX5,WHS,WHSC1
FUSION GENES

DNA/RNA

Description

Spans 120 Kb of genomic DNA and consists of 24 exons transcribed into a mRNA that undergoes alternative splicing (Marango et al., 2007).

Transcription

Undergoes complex alternative splicing. Most primary trancripts splice directly to exon 3, which contains the proper translation initiation site, though small fraction of transcripts retain upstream sequence including exons 1 and 2 (Keats et al., 2005).

Proteins

Atlas Image
Conserved domains present in MMSET variants (adapted from Keats et al., 2005).

Description

Alternative splicing of exon 4 to 4a instead of 5 generates de MMSET III protein (273 amino acids, 32 kDa), due to the presence of an in-frame stop codon in exon 4a. Alternative splicing of exon 10 to 11 or 12 generates MMSET I (647 amino acids, 75 kDa) or the full-length MMSET II (1365 amino acids, 155 kDa) respectively, due to the presence of an in-frame stop codon in exon 11. A third transcript initiated within a middle intron of MMSET, encoding a mRNA comprising the 3half of MMSET gene was identified and encodes a protein named RE-IIBP.
The long transcript, MMSET II, contains: 2 PWWP (proline-tryptophan-tryptophan-proline) domain, a HMG box (high mobility group), 4 PHD (plant-home domain)- type zinc finger motifs and a SET domain. MMSET I contains only a PWWP and a HMG domain and REIIBP, 2 PHD, a PWWP and a SET domain (Keats et al., 2005).

Expression

Widely expressed.
It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients (Stec et al., 1998). Recently it has been shown that MMSET is highly expressed in different tumor types such as carcinomas of the gastrointestinal tract (stomach, colon, anal canal), small cell lung carcinoma, bladder, female genitals and skin (Hudlebusch et al., 2011). It is also highly expressed and associated with aggressive neuroblastoma (Hudlebusch et al., 2011).

Localisation

Homogenous pattern within the nucleus, excluded from the nucleolus.

Function

Histone methyltransferase that leads to dimethylation of histone 3 lysine 36 (H3K36) (Marango et al., 2008; Martinez-Garcia et al., 2011; Kuo et al., 2011). WHSC1 is involved in the cellular response to DNA damage through its activity on H4K20 residue (Hajdu et al., 2011; Pei et al., 2011).

Implicated in

Entity name
Note
WHSC1 was identified as a gene involved in the t(4;14)(p16;q32) translocation present in approximately 15% to 20% of MM (Chesi et al., 1998). This subtype of myeloma with t(4;14)(p16;q32) has a poor prognosis with frequent relapse after autologous stem-cell transplantation (Moreau et al., 2002; Chang et al., 2004).
Atlas Image
The t(4;14) Translocation Identifies MMSET as an oncogene in Multiple Myeloma. The gene rearrangement links the Eµ enhancer 5 to MMSET, driving transcription of MMSET from the telomeric-centromeric direction. The reciprocal translocation links an Ig enhancer 3 to the FGFR3 locus stimulating transcription in the centromeric-telomeric direction.
Entity name
Glioblastoma
Note
WHSC1 expression level is correlated with glioma grade, and it appears to be directly involved in the proliferative capacity of GBM cells in vitro (Li et al., 2008).
Entity name
Neuroblastoma
Note
MMSET is highly expressed in 75% neuroblastomas and is associated with aggressiveness. MMSET is associated with poor prognostic markers, poor survival, and progression; and is required for proliferation of neuroblastoma cells (Hudlebusch et al., 2011).
Entity name
Urinary bladder cancer
Note
In urinary bladder cancer, MMSET protein was detected in 40% of the cases and was associated with aggressiveness: expression levels correlated with poor prognostic markers (stage, grade, age, and type of tumor growth), and progression (Hudlebusch et al., 2011).
Entity name
Prostate cancer
Note
Analysis of microarray databases indicates that MMSET expression rises in the progression from benign prostatic epithelium to localized and metastatic PCa. Overexpression of MMSET in RWPE-1 cells is accompanied by an epithelial to mesenchymal transition (EMT), characterized by a change in cell morphology and increased expression of mesenchymal markers vimentin and N-cadherin. Twist1, an EMT promoting gene, was strongly regulated by MMSET (Ezponda-Itoiz et al., 2012).
Entity name
Wolf-Hirschhorn syndrome (WHS)
Note
Wolf-Hirshhorn syndrome is caused by a partial deletion of chromosome 4p, particularly in the region of WHSC1 and WHSC2. About 87% of cases represent a de novo deletion, while about 13% are inherited from a parent with a chromosome translocation.

Bibliography

Pubmed IDLast YearTitleAuthors
150159702004The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant.Chang H et al
97871351998The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts.Chesi M et al
227970642013The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer.Ezponda T et al
217885152011Wolf-Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage.Hajdu I et al
215275572011MMSET is highly expressed and associated with aggressiveness in neuroblastoma.Hudlebusch HR et al
156775572005Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients.Keats JJ et al
220993082011NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming.Kuo AJ et al
181826272008Identification of a novel proliferation-related protein, WHSC1 4a, in human gliomas.Li J et al
181564912008The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor.Marango J et al
209746712011The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells.Martinez-Garcia E et al
121768742002Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy.Moreau P et al
212933792011MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites.Pei H et al
96181631998WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.Stec I et al

Other Information

Locus ID:

NCBI: 7468
MIM: 602952
HGNC: 12766
Ensembl: ENSG00000109685

Variants:

dbSNP: 7468
ClinVar: 7468
TCGA: ENSG00000109685
COSMIC: NSD2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000109685ENST00000312087O96028
ENSG00000109685ENST00000353275O96028
ENSG00000109685ENST00000382888O96028
ENSG00000109685ENST00000382891O96028
ENSG00000109685ENST00000382892O96028
ENSG00000109685ENST00000382895O96028
ENSG00000109685ENST00000398261O96028
ENSG00000109685ENST00000420906O96028
ENSG00000109685ENST00000436793O96028
ENSG00000109685ENST00000503128O96028
ENSG00000109685ENST00000507820D6RFE7
ENSG00000109685ENST00000508803O96028
ENSG00000109685ENST00000509115D6R9V2
ENSG00000109685ENST00000511904H0Y9L4
ENSG00000109685ENST00000512700O96028
ENSG00000109685ENST00000514045O96028
ENSG00000109685ENST00000514329H0Y9U6
ENSG00000109685ENST00000515806D6RIS1

Expression (GTEx)

0
5
10
15
20
25
30
35

Pathways

PathwaySourceExternal ID
Lysine degradationKEGGko00310
Lysine degradationKEGGhsa00310
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
G2/M DNA damage checkpointREACTOMER-HSA-69473
DNA RepairREACTOMER-HSA-73894
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
PKMTs methylate histone lysinesREACTOMER-HSA-3214841
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
DNA Double Strand Break ResponseREACTOMER-HSA-5693606
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksREACTOMER-HSA-5693565
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
Processing of DNA double-strand break endsREACTOMER-HSA-5693607
Nonhomologous End-Joining (NHEJ)REACTOMER-HSA-5693571

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
212933792011MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites.177
209746712011The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells.135
220993082011NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming.134
181564912008The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor.69
156775572005Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients.63
179427562008The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity.57
213859302011The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors.56
231597372013Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer.56
227970642013The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer.52
238236602014Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies.51

Citation

Eva Martinez-Garcia ; Jonathan D Licht

NSD2 (nuclear receptor binding SET domain protein 2 )

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: http://atlasgeneticsoncology.org/gene/42809/nsd2

Historical Card

2008-11-01 NSD2 (nuclear receptor binding SET domain protein 2 ) by  Eva Martinez-Garcia,Jonathan D Licht 

Feinberg School of Medicine, Northwestern University, Hematology\\\/Oncology Division, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA