The SMYD3 gene is comprised of 12 exons, spanning 757.8 kb on chromosome 1q44. Two transcript variants were encoded using different first exon and promoter.
A variable number of tandem repeats (VNTR) polymorphism in E2F-1-binding element in the promoter region of SMYD3 transcript variant 1 has been shown to be significantly associated with an increased risk of colorectal cancer, hepatocellular carcinoma and breast cancer in Japanese population (Tsuge et al., 2005). It is also shown that this VNTR polymorphism might be a susceptibility factor for human esophageal squamous cell carcinoma in relation to tobacco smoking (Wang H et al., 2008). However, it seemed that this polymorphism was not associated with the cancer risk in all the races in the world (Frank et al., 2006; Wang et al., 2007).
A copy-number variation (CNV) on chromosome 1 was observed to be proximal to SMYD3 that displayed high expression in the lymphoblastoid cell lines, and this CNV was significantly associated with 1-beta-D-arabinofuranosylcytosine cytotoxicity (Kalari et al., 2010).

The SMYD3 gene mainly has two transcript variants of 1641 and 1469 bp, each comprising 12 exons. They differ for the alternative usage of the different first exon and promoter. The variant 2 is shorter at the N-terminus, compared to the variant 1. Besides, there was a report showed that another SMYD3 transcript variant, termed SMYD3-NY, was detected in adult human testis and spermatozoa using the methods of hybridization with a human cDNA microarray (Zhou et al., 2005). However, SMYD3-NY has not been further confirmed with experimental evidence yet.

Not yet described.

The 1641 bp transcript variant 1 encodes a 428 amino acids protein containing a zf-MYND domain (49-87) and a SET domain (148-239), the transcript variant 2 uses a downstream translational start codon and encodes a 369 amino acids protein which is 100% identical with the 60-428 region of the isoform 1.
It has been shown that human cancer cells also express a cleaved form of SMYD3 lacking the 34 amino acids in the N-terminal region of the full-length SMYD3 isoform 1. It seems that the N-terminal region of SMYD3 isoform 1 plays an important role for the regulation of its methyltransferase activity, and the cleavage of 34 amino acids in the N-terminal region or interaction with heat shock protein 90 alpha (HSP90alpha) may enhance the histone methyltransferase (HMTase) activity compared to the full-length protein (Silva et al., 2008).

SMYD3 is frequently up-regulated in colorectal carcinoma, hepatocellular carcinoma and breast cancer (Hamamoto et al., 2004; Hamamoto et al., 2006). miR-124 can down-regulate SMYD3 through binding to 3 UTR of SMYD3 protein (Furuta et al., 2010).

The SMYD3 protein is located mainly in the cytoplasm when the cells are arrested at G0/G1, but accumulated in the nuclei at S phase and G2/M (Hamamoto et al., 2004).

SMYD3 is a SET-domain-containing lysine histone methyltransferase which has been regarded as an important factor in carcinogenesis. Formed a complex with RNA polymerase II through an interaction with the RNA helicase HELZ, SMYD3 specifically methylates histone H3 at lysine 4 and activates the transcription of a set of downstream genes (including of Nkx2.8, hTERT, WNT10B, VEGFR1, c-Met, etc) containing a "5 - CCCTCC - 3" or "5 - GGAGGG - 3" sequence in the promoter region, and these activities require protein cofactors HSP90alpha (Hamamoto et al., 2004; Liu et al., 2007; Hamamoto et al., 2006; Kunizaki et al., 2007; Zou et al., 2009). Enhanced expression of SMYD3 is essential for the growth of many cancer cells (such as colorectal carcinoma, hepatocellular carcinoma, breast cancer, etc), and it also could stimulate cell adhesion and migration, whereas suppression of SMYD3 by RNAi or other reagents induces apoptosis and inhibits cell proliferation and migration (Hamamoto et al., 2004; Hamamoto et al., 2006; Luo et al., 2007; Wang SZ et al., 2008; Zou et al., 2009; Chen et al., 2007; Luo et al., 2010).
SMYD3 may be an important coactivator of estrogen receptor (ER) in the estrogen signal pathway. It can directly interact with the ligand binding domain of ER, in turn augments ER target gene expression via histone H3-K4 methylation (Kim et al., 2009). Besides, it has been shown that SMYD3 could interact with Jab1 in yeast cells and in vitro, and might be required for Jab1-mediated enhancement of hemotopoietic progenitors cells (Mori et al., 2008).

SMYD3 displays structural homologies with other members of the SMYD histone methyltransferase family, such as the SMYD1 (30% identity, 50% similarity), SMYD2 (32% identity, 52% similarity), SMYD4 and SMYD5.

Not yet described. A VNTR polymorphism in the 5 flanking region of SMYD3 has been reported as we mentioned in the "DNA Description" section.