Structure, Activity and Function of the Suv39h1 and Suv39h2 Protein Lysine Methyltransferases

Abstract

SUV39H1 and SUV39H2 were the first protein lysine methyltransferases that were identified more than 20 years ago. Both enzymes introduce di- and trimethylation at histone H3 lysine 9 (H3K9) and have important roles in the maintenance of heterochromatin and gene repression. They consist of a catalytically active SET domain and a chromodomain, which binds H3K9me2/3 and has roles in enzyme targeting and regulation. The heterochromatic targeting of SUV39H enzymes is further enhanced by the interaction with HP1 proteins and repeat-associated RNA. SUV39H1 and SUV39H2 recognize an RKST motif with additional residues on both sides, mainly K4 in the case of SUV39H1 and G12 in the case of SUV39H2. Both SUV39H enzymes methylate different non-histone proteins including RAG2, DOT1L, SET8 and HupB in the case of SUV39H1 and LSD1 in the case of SUV39H2. Both enzymes are expressed in embryonic cells and have broad expression profiles in the adult body. SUV39H1 shows little tissue preference except thymus, while SUV39H2 is more highly expressed in the brain, testis and thymus. Both enzymes are connected to cancer, having oncogenic or tumor-suppressive roles depending on the tumor type. In addition, SUV39H2 has roles in the brain during early neurodevelopment.

PIP4K2B is a mechanosensor and induces heterochromatin-driven nuclear softening through UHRF1

“…We then focused our attention on two genes whose expression was decreased in both sh_PIP4K2B and Soft (cluster 3): SUV39H1 and UHRF1 (Figure 3B and Supplementary Figure 5C and 5D). The first encodes a histone methyltransferase which methylates H3K9me2 into H3K9me3 allowing heterochromatin formation (41). The second encodes for a multidomain nuclear E3-ubiquitin ligase involved in heterochromatin organization, taking part in H3K9 binding of SUV39H1 itself, and in the recruitment of DNA methyltransferases to control DNA methylation (42).…”

Heterochromatin in the fungal plant pathogen, Zymoseptoria tritici: Control of transposable elements, genome plasticity and virulence

“…Thirdly, do all of the phenotypes associated with deletion of kmt1 and kmt6 result from loss of histone modifications? Mammalian Suv39H1 and Ezh2 KMTases both have non-histone substrates ( Rodriguez-Paredes and Lyko, 2019 ; Weirich et al, 2021 ) and the possibility that this is the case for Z. tritici Kmt1 and Kmt6 needs to be considered. Finally, to what extent does the remodelling of heterochromatin during infection regulate the expression of effector genes ( Soyer et al, 2019 ; Meile et al, 2020 ) and what are the environmental cues and signalling pathways that control this process?…”

The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy

“…The variant suppressor 39 homolog 1 (SUV39H1), also known as KMT1A, is responsible for the introduction of the dimethylation and trimethylation of histone 3 lysine 9 (H3K9me3) ( 67 ). It mainly disrupts some important gene regulatory elements in tumor cells and reduces the sensitivity to immune response.…”