SETD2

The SETD2 gene, also known as HYPB, HSPC069, HBP231 or KMT3A, is located in the 2nd and 1st bands of human short chromosome 3 (3p21.31) and is approximately 147kb in length, including 23 exons and 22 Intron. The SETD2 gene was originally found in human CD34+ hematopoietic stem/progenitor cells (HSPCs) and cloned and named HSPC069. At the same time, studies have shown that the C-terminus of its encoded protein interacts with the Huntington disease (HD) protein Huntington and participates in the pathological process of HD. It is also named Huntington's interacting protein (HYPB). The Northernblot assay showed that the HYPB gene is expressed in almost all tissues. The protein encoded by the HYPB gene is conserved in yeast and vertebrate tissues and contains a conserved SET domain that selectively regulates the lysine methylation of histone 3 at position 36, while the HYPB protein passes through its WW domain. The hyperphosphorylated RNA polymerase II binds to and activates the transcription process and is therefore renamed SETD2.
The SETD2 protein consists of 2564 amino acid residues with a molecular mass of approximately 290 kDa and is expressed in various tissues and organs such as bone marrow, kidney, breast and bladder. The SETD2 protein consists mainly of six domains:
The SET( Su( var)3 ~9, enhancer of zeste (E(z)) and trithorax ( trx)) domain contains approximately 130 amino acid residues and is evolutionarily conserved with histone methyltransferase (HMTase) active;
AWS ( associate with SET) domain;
The PostSET domain is a cysteine-rich motif after a SET domain, and the AWS domain is located on both sides of the SET domain to form an AWS-SET-PostSET triple domain to exert HMTase effect;
LCR (low-charge region) domain, including 230 amino acid residues, the majority of amino acids in this region are not charged;
The WW domain is located at the C-terminus and contains 127 amino acid residues and is widely expressed in eukaryotes, interacting with proline-rich fragments and SH3 motif proteins;
The SRI (Set2 Rpb1 Interacting) domain is located at the end of the C-terminus of SETD2 and interacts with RNA polymerase II C-terminal repeat domain (CTD) and is associated with histone methylation.
The main physiological functions include:
Histone methylation modification and transcriptional regulation: The SET domain of SETD2 is evolutionarily conserved and can methylate lysine at position 36 of histone 3, specifically catalyzing H3K36me3. SETD2 and H3K36me3 play a role in vascular development, embryonic stem cell differentiation and embryo implantation;
Maintaining genomic stability and DNA damage repair: Histone modifications play an important role in the repair of DNA double-strand breaks (DSBs). Studies have shown that the SETD2 gene frameshift mutation is associated with high microsatellite instability (MSI) in rectal cancer.