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

•An overview on the substrates of SET domain-containing proteins is provided.•Protein complexes of SET domain-containing proteins are described.•Biological functions of different classes of SET domain-containing proteins are discussed.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 enzymes that have been reported to modify non-histone substrates.