The World of SET ‐Containing Lysine Methyltransferases

Abstract

Genomic DNA (deoxyribonucleic acid) in eukaryotic cells is compacted into chromatin that plays an important role in regulation of DNA replication, gene expression, recombination and repair. Chromatin is composed of nucleosomes – genomic DNA – wrapped around two copies of each of the four canonical histones: H2A, H2B, H3 and H4. The amino‐terminal tails of histones undergo multiple post‐translational modifications such as methylation, acetylation, phosphorylation, ADP (adenosine diphosphate)‐ribosylation and ubiquitination, resulting in chromatin remodeling. Lysine methylation of histones is a post‐translational modification playing a key role in regulation of gene expression and chromatin functioning. Each type of histones undergoes methylation at various lysines by SET domain‐containing methyltransferases (KMTs). These modifications act in a combinatorial or sequential manner with other histone modifications conforming to the ‘histone code’ hypothesis. Such interplay between histone modifications determines unique functional consequences for gene expression, DNA replication and mitosis. Importantly, KMTs are also able to methylate non‐histone targets, for example, important transcription factors, TP53, E2F1 and others, affecting their protein stability and activity. Key Concepts The amino‐terminal tails of histones undergo multiple post‐translational modifications. In particular, methylation of lysines in histones is a post‐translational modification regulating gene expression, chromatin remodeling, DNA methylation and non‐histone protein function. Each type of histones undergoes methylation by SET lysine methyltransferases at various sites: Lys26, Lys121, Lys129, Lys159, Lys171, Lys177 and Lys192 in histone H1B; Lys5, Lys13 and Lys15 in histone H2A; Lys15 in histone H2B; Lys4, Lys9, Lys27, Lys36 and Lys79 in histone H3; and Lys20 and Lys59 in histone H4. Different extent of methylation on multiple lysines within histones is associated with various transcriptional outcomes ranging from activation to complete repression of genes. Different numbers of methyl groups on target lysines are recognised by special protein domains within transcription‐related proteins, which facilitate the formation of protein complexes on chromatin. Defects in SET methyltransferases enzymes can lead to cancer, neurological disorders, growth and developmental defects and other human pathologies.

The Role of Lysine Methyltransferase SET7/9 in Proliferation and Cell Stress Response

“…Posttranslational histone modifications such as methylation, phosphorylation, acetylation, ubiquitination and ADP-ribosylation define chromatin’s dynamic structure and function. Histones as substrates for lysine methylation were first described in 1964 [ 28 ]. In particular, lysines H3K4, H3K9, H3K27, H3K36 and H4K20 are the preferred sites for methylation [ 28 , 29 ].…”

“…Histones as substrates for lysine methylation were first described in 1964 [ 28 ]. In particular, lysines H3K4, H3K9, H3K27, H3K36 and H4K20 are the preferred sites for methylation [ 28 , 29 ]. SET7/9 was initially identified as a methyltransferase that methylates H3K4 facilitating transcriptional activation by displacing the histone deacetylase NuRD complex (HDAC) [ 1 ], ( Table 1 ).…”