Trends in Biochemical Sciences
ReviewFeature ReviewSET for life: biochemical activities and biological functions of SET domain-containing proteins
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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