SET for life: biochemical activities and biological functions of SET domain-containing proteins

Abstract

SET domain-containing proteins belong to a group of enzymes named after a common domain that utilizes the cofactor S-adenosyl-L-methionine (SAM) to achieve methylation of its substrates. Many SET domain-containing proteins have been shown to display catalytic activity towards particular lysine residues on histones, but emerging evidence also indicates that various non-histone proteins are specifically targeted by this clade of enzymes. Here, we summarize the most recent findings on the biological functions of the major families of SET domain-containing proteins catalyzing the methylation of histones 3 on lysines 4, 9, 27, and 36 (H3K4, H3K9, H3K27, and H3K36) and histone 4 on lysine 20 (H4K20) as well as candidates that have been reported to regulate non-histone substrates.

Keywords: SET domain-containing proteins; histone lysine methylation; non-histone substrates.

Figure 1. Relationship and structure of human SET domain-containing proteins

51 human SET domain-containing proteins were aligned according to their annotated SET domain by using ClustalO v. 1.1.0. The length of each tree branch to the next branch point constitutes a readout for the unit change per amino acid as displayed on the axis at the bottom of the tree. For each SET domain-containing protein the name(s) and corresponding domain structure are provided. The allocation and annotation of each domain structure follows SMART or NCBI (for PRDM10, SETD3, SETD4 and SETD9) as accessed on April 9, 2013. Symbols and names for depicted domains are displayed in the box labeled “Domains”. Approximately 2000 amino acids (∼2K aa) from the domain structure of MLL3 and MLL4 were removed as indicated by two parallel slashes. SET domain-containing proteins that show specificity towards the same histone residue (see also Figure 2) are highlighted in the same color. Colors are: green: histone H3K4 lysine methyltransferases (KMTs); red: H3K9 KMTs; orange: H3K27 KMTs; blue: H3K36 KMTs; purple: H4K20 KMTs.

Figure 2. Histone lysine methyltransferase target specificities of mammalian SET domain-containing proteins

Green: H3K4 histone lysine methyltransferases (KMTs); red: H3K9 KMTs; orange: H3K27 KMTs; blue: H3K36 KMTs; purple: H4K20 KMTs. Non-histone substrates have been described for members of all five KMT families, SETD7 and other SET domain-containing proteins. A summary of all non-histone targets described to date can be found in Tables 1-3.

Figure 3. Mammalian protein complexes of SET domain-containing proteins described to date

All SET domain-containing proteins are highlighted in red. (a) Six COMPASS-like complexes for mammalian H3K4 KMTs have been described consisting of three “subbranches” (SET1A/B, MLL1/2 and MLL3/4). All complexes share core subunits which are indicated in green. Complex-specific subunits are highlighted in blue. All mammalian COMPASS-like complexes additionally contain HCFC1 highlighted in gray which is not conserved in yeast. (b) Four complexes for mammalian H3K9 KMTs have been reported: a heterodimeric G9A/GLP complex together with the multi-zinc finger protein WIZ; an S-phase specific SETDB1 complex with the subunits MBD1, the chromatin assembly factor subunits CHAF1 A, CHAF1B, RBBP4 and the subunits TRIM28 and HP1α; a SETDB1 complex with the subunits MBD1, ATF7IP1 and ATF7IP2; a quaternary mega complex consisting of the H3K9 KMTs G9A, GLP, SUV30H1, SETDB1 and HP1β, HP1γ (c) H3K27 KMT complexes consist of either EZH1 or EZH2, the core subunits RBBP4 or RBBP7, SUZ12, EED (highlighted in green) and accessory factors such as AEBP2 (gray), PCL1 or PCL2 or PCL3 (all in blue) and JARID2 (orange) that either modulate PRC2 activity and/or are required for the context-specific recruitment of PRC2 to chromatin.