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

https://doi.org/10.1016/j.tibs.2013.09.004Get rights and content

Highlights

  • 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.

Section snippets

SET domain-containing proteins

SET domain-containing proteins exist in all eukaryotes studied to date. This protein family is characterized by an approximately 130 amino acid-long domain called the SET domain, which was named after the Drosophila proteins Suppressor of variegation 3–9 [Su(var)3–9], Enhancer of zeste [E(z)], and Trithorax (Trx). The SET domain possesses catalytic activity towards the ɛ-amino group of lysine residues. Depending on the context and their biochemical properties, SET domain-containing proteins are

Substrate specificity

H3K4 KMTs are conserved in plants, yeast, Drosophila, and mammals. Yeast Set1 is the sole enzyme that catalyzes the mono-, di-, and trimethylation of H3K4 1, 2. In Drosophila, yeast Set1 is represented by three homologous proteins: Set1, Trithorax (Trx), and Trithorax-related (Trr). Mammals contain six yeast Set1-related proteins with SET1A and SET1B (related to Drosophila Set1); MLL1 and MLL2 (related to Drosophila Trx); and MLL3 and MLL4 (related to Drosophila Trr) [1] (Figure 1). Drosophila

Substrate specificity

SUV39H1 was the first SET domain-containing protein reported to contain methyltransferase specificity in general and towards H3K9 in particular 66, 67, 68. Subsequently, the list of H3K9 KMTs has been expanded considerably and, in mammals, now includes SUV39H1, SUV39H2, G9A, GLP, SETDB1, SETDB2, PRDM3, and PRDM16 66, 67, 68, 69 (Figure 1, Figure 2). PRDM3 and PRDM16 are members of the PRDM family and contain an N-terminal PR domain, which is closely related to the SET domain 70, 71. With a

Substrate specificity

Drosophila E(z) is a member of the Polycomb group of proteins functioning in the negative regulation of genes that are crucial for the developmental patterning of organisms – the so-called homeotic genes 120, 121, 122. Later, it was shown that E(z) and its mammalian homologs, EZH1 and EZH2 (Figure 1, Figure 2), are the catalytically active components of a protein complex named Polycomb repressive complex 2 (PRC2), which is able to methylate H3K27 [120] (Figure 2). E(z) null mutant larvae in

Substrate specificity

In mammalian cells, H3K36 KMTs include SET2 (SETD2), NSD1, NSD2 (WHSC1, MMSET), NSD3 (WHSC1L), ASH1L [178], and SETMAR [179] (Figure 1). Set2/SET2 is conserved from yeast to mammals, whereas NSD1–3 and ASH1L are homologous to Maternal effect sterile 4 (Mes-4)/MES-4 and Ash1/LIN-59 in Drosophila and C. elegans 178, 180, 181, 182, 183. In yeast, Set2 is required for all of the mono-, di-, and trimethylation of H3K36 184, 185. C. elegans, Drosophila, and mammalian Set2/SET2 constitute a major

Substrate specificity

X-ray crystallographic studies of SETD8 (PR-SET7, SET8) in combination with nuclear magnetic resonance and in vitro assays on recombinant nucleosomes indicate that SETD8 is a major H4K20 monomethyltransferase 213, 214. In mice, Suv420h1 and Suv420h2 are redundantly required to implement bulk H4K20 di- and trimethylation 215, 216 (Figure 1, Figure 2). Implementation of H4K20 monomethylation by Setd8 is essential for proper H4K20 di- and trimethylation via Suv420h1/2 [217]. Therefore, not

Concluding remarks

The involvement of SET domain-containing proteins in many diverse mechanisms such as transcriptional regulation, enhancer function, mRNA splicing, DNA replication, and the DNA damage response (Box 4) either by means of methylating histones or targeting non-histone substrates (Table 1, Table 2, Table 3, Box 1, Box 2) highlights the importance of this protein family in maintaining proper tissue homeostasis. Therefore, not surprisingly, the misregulation of certain histone methylation marks and

Acknowledgments

We thank Drs Edwin Smith and Marc Morgan for insightful discussions and for the critical reading of this manuscript, and Lisa Kennedy for editorial assistance. Studies in Shilatifard's laboratory regarding the subject of this review are supported in part by funding through National Institutes of Health grants R01CA150265, R01CA89455, and R01GM069905 to A.S.

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