SMYD3

SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (myeloid-Nervy-DEAF-1) domain-containing protein 3 is a protein that in humans is encoded by the SMYD3 gene.[5]

SMYD3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3MEK, 3OXF, 3OXG, 3OXL, 3PDN, 3QWP, 3RU0, 5CCL, 5CCM, 5EX0, 5EX3, 5HI7, 5HQ8
Identifiers
Aliases	SMYD3, KMT3E, ZMYND1, ZNFN3A1, bA74P14.1, SET and MYND domain containing 3
External IDs	OMIM: 608783 MGI: 1916976 HomoloGene: 41491 GeneCards: SMYD3
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q44 Start 245,749,342 bp[1] End 246,507,312 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 H4|1 83.48 cM Start 178,951,960 bp[2] End 179,518,041 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • metal ion binding • methyltransferase activity • transferase activity • RNA polymerase II core binding • RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding • GO:0001948 protein binding • histone-lysine N-methyltransferase activity • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding Cellular component • cytoplasm • cell nucleus • nucleoplasm • cytosol Biological process • cellular response to dexamethasone stimulus • nucleosome assembly • histone lysine methylation • methylation • myotube cell development • negative regulation of protein kinase activity • positive regulation of peptidyl-serine phosphorylation • positive regulation of transcription from RNA polymerase II promoter • establishment of protein localization • chromatin organization Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	64754	69726
Ensembl	ENSG00000185420	ENSMUSG00000055067
UniProt	Q9H7B4	Q9CWR2
RefSeq (mRNA)	NM_001167740 NM_022743	NM_027188
RefSeq (protein)	NP_001161212 NP_073580 NP_001362891 NP_001362892 NP_001362894 NP_001362895	NP_081464
Location (UCSC)	Chr 1: 245.75 – 246.51 Mb	Chr 1: 178.95 – 179.52 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

SMYD3 is a lysine methyltransferase[6] which specifically methylates H3K4 and H4K5.[7] SMYD3 plays a role in transcriptional regulation as a member of an RNA polymerase complex.[5] It is also involved in cancer regulation.[6]

Expression

SMYD3 is predominantly expressed in skeletal muscles and the testis.

Model organisms

Smyd3 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Brain histopathology	Normal
Salmonella infection	Normal[8]
Citrobacter infection	Normal[9]
All tests and analysis from[10][11]

Model organisms have been used in the study of SMYD3 function. A conditional knockout mouse line, called Smyd3^{tm2a(KOMP)Wtsi}[12][13] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[14][15][16]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[10][17] Twenty three tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[10]

Interactions

SMYD3 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1[18] and POLR2A.[18]

SMYD3 trimethylates a lysine residue on MAP3K2, which causes crosstalk into the MAP kinase signaling pathway in Ras-driven cancers.[19]

Link to cancer

SMYD3 plays an important role in the progression of cancers in humans. It is highly overexpressed in a number of cancers such as liver, breast, and colorectal carcinomas.[20] SMYD3 is known to play a role in lung, esophegeal and prostate cancers also.[21]

It has been noted that in lung and colorectal cancers, MAP3K2 methylation by SMYD3 ameliorates PPA2's inhibitory control, which leads to the overriding of apoptosis signals via the activation of the MEK/ERK signalling cascade.[22] Meanwhile, in colon and liver cancers, SMYD3-mediated methylation of H3 promotes RNAP II recruitment and the associated transcription factors from proto-oncogenic regions.[21]

References

1. GRCh38: Ensembl release 89: ENSG00000185420 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000055067 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: SMYD3 SET and MYND domain containing 3".
6. Van Aller GS, Reynoird N, Barbash O, Huddleston M, Liu S, Zmoos AF, et al. (April 2012). "Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation". Epigenetics. 7 (4): 340–3. doi:10.4161/epi.19506. PMC 3368817. PMID 22419068.
7. Liu Y, Liu H, Luo X, Deng J, Pan Y, Liang H (June 2015). "Overexpression of SMYD3 and matrix metalloproteinase-9 are associated with poor prognosis of patients with gastric cancer". Tumour Biology. 36 (6): 4377–86. doi:10.1007/s13277-015-3077-z. PMID 25627005.
8. "Salmonella infection data for Smyd3". Wellcome Trust Sanger Institute.
9. "Citrobacter infection data for Smyd3". Wellcome Trust Sanger Institute.
10. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
11. Mouse Resources Portal, Wellcome Trust Sanger Institute.
12. "International Knockout Mouse Consortium".
13. "Mouse Genome Informatics".
14. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al. (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
15. Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
16. Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
17. van der Weyden L, White JK, Adams DJ, Logan DW (June 2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
18. Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, et al. (August 2004). "SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells". Nature Cell Biology. 6 (8): 731–40. doi:10.1038/ncb1151. PMID 15235609.
19. Mazur PK, Reynoird N, Khatri P, Jansen PW, Wilkinson AW, Liu S, et al. (June 2014). "SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer". Nature. 510 (7504): 283–7. doi:10.1038/nature13320. PMC 4122675. PMID 24847881.
20. Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, et al. (August 2004). "SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells". Nature Cell Biology. 6 (8): 731–40. doi:10.1038/ncb1151. PMID 15235609.
21. Giakountis A, Moulos P, Sarris ME, Hatzis P, Talianidis I (February 2017). "Smyd3-associated regulatory pathways in cancer". Seminars in Cancer Biology. 42: 70–80. doi:10.1016/j.semcancer.2016.08.008. PMID 27554136.
22. Colón-Bolea P, Crespo P (December 2014). "Lysine methylation in cancer: SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK pathway". BioEssays. 36 (12): 1162–9. doi:10.1002/bies.201400120. PMID 25382779.

Further reading

• Lehner B, Semple JI, Brown SE, Counsell D, Campbell RD, Sanderson CM (January 2004). "Analysis of a high-throughput yeast two-hybrid system and its use to predict the function of intracellular proteins encoded within the human MHC class III region". Genomics. 83 (1): 153–67. doi:10.1016/S0888-7543(03)00235-0. PMID 14667819.
• Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, et al. (August 2004). "SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells". Nature Cell Biology. 6 (8): 731–40. doi:10.1038/ncb1151. PMID 15235609.
• Zhou Z, Ren X, Huang X, Lu L, Xu M, Yin L, et al. (2006). "SMYD3-NY, a novel SMYD3 mRNA transcript variant, may have a role in human spermatogenesis". Annals of Clinical and Laboratory Science. 35 (3): 270–7. PMID 16081583.
• Tsuge M, Hamamoto R, Silva FP, Ohnishi Y, Chayama K, Kamatani N, et al. (October 2005). "A variable number of tandem repeats polymorphism in an E2F-1 binding element in the 5' flanking region of SMYD3 is a risk factor for human cancers". Nature Genetics. 37 (10): 1104–7. doi:10.1038/ng1638. PMID 16155568.
• Hamamoto R, Silva FP, Tsuge M, Nishidate T, Katagiri T, Nakamura Y, Furukawa Y (February 2006). "Enhanced SMYD3 expression is essential for the growth of breast cancer cells". Cancer Science. 97 (2): 113–8. doi:10.1111/j.1349-7006.2006.00146.x. PMID 16441421.
• Wang XQ, Miao X, Cai Q, Garcia-Barcelo MM, Fan ST (March 2007). "SMYD3 tandem repeats polymorphism is not associated with the occurrence and metastasis of hepatocellular carcinoma in a Chinese population". Experimental Oncology. 29 (1): 71–3. PMID 17431393.