Histone methyltransferase
| Histone-lysine N-methyltransferase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
Histone methyltransferases (HMT) are histone-modifying
The genomic DNA of eukaryotes associates with histones to form chromatin.[8] The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones.[9] Histone methylation is a principal epigenetic modification of chromatin[9] that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.[2]
Types
The class of lysine-specific histone methyltransferases is subdivided into SET domain-containing and non-SET domain-containing. As indicated by their monikers, these differ in the presence of a SET domain, which is a type of protein domain.
Human genes encoding proteins with histone methyltransferase activity include:
- ASH1L
- DOT1L
- EHMT1, EHMT2, EZH1, EZH2
- MLL5
- NSD1
- PRDM2
- SETMAR, SMYD1, SMYD2, SMYD3, SMYD4, SMYD5, SUV39H1, SUV39H2, KMT5B, SUV420H2
SET domain-containing lysine-specific
Structure
The structures involved in methyltransferase activity are the SET domain (composed of approximately 130 amino acids), the pre-SET, and the post-SET domains. The pre-SET and post-SET domains flank the SET domain on either side. The pre-SET region contains cysteine residues that form triangular zinc clusters, tightly binding the zinc atoms and stabilizing the structure. The SET domain itself contains a catalytic core rich in β-strands that, in turn, make up several regions of β-sheets. Often, the β-strands found in the pre-SET domain will form β-sheets with the β-strands of the SET domain, leading to slight variations to the SET domain structure. These small changes alter the target residue site specificity for methylation and allow the SET domain methyltransferases to target many different residues. This interplay between the pre-SET domain and the catalytic core is critical for enzyme function.[1]
Catalytic mechanism
In order for the reaction to proceed, S-Adenosyl methionine (SAM) and the lysine residue of the substrate histone tail must first be bound and properly oriented in the catalytic pocket of the SET domain. Next, a nearby tyrosine residue deprotonates the ε-amino group of the lysine residue.[10] The lysine chain then makes a nucleophilic attack on the methyl group on the sulfur atom of the SAM molecule, transferring the methyl group to the lysine side chain.
Non-SET domain-containing lysine-specific
Instead of SET, non-SET domain-containing histone methyltransferase utilizes the enzyme Dot1. Unlike the SET domain, which targets the lysine tail region of the histone, Dot1 methylates a lysine residue in the globular core of the histone, and is the only enzyme known to do so.[1] A possible homolog of Dot1 was found in archaea which shows the ability to methylate archaeal histone-like protein in recent studies.
Structure
The N terminal of Dot1 contains the active site. A loop serving as the binding site for SAM links the N-terminal and the C-terminal domains of the Dot1 catalytic domain. The C-terminal is important for the substrate specificity and binding of Dot1 because the region carries a positive charge, allowing for a favorable interaction with the negatively charged backbone of DNA.[11] Due to structural constraints, Dot1 is only able to methylate histone H3.
Arginine-specific
There are three different types of
Structure
The catalytic domain of PRMTs consists of a SAM binding domain and substrate binding domain (about 310 amino acids in total).[5][6][7] Each PRMT has a unique N-terminal region and a catalytic core. The arginine residue and SAM must be correctly oriented within the binding pocket. SAM is secured inside the pocket by a hydrophobic interaction between an adenine ring and a phenyl ring of a phenylalanine.[7]
Catalytic mechanism
A glutamate on a nearby loop interacts with nitrogens on the target arginine residue. This interaction redistributes the positive charge and leads to the deprotonation of one nitrogen group,[16] which can then make a nucleophilic attack on the methyl group of SAM. Differences between the two types of PRMTs determine the next methylation step: either catalyzing the dimethylation of one nitrogen or allowing the symmetric methylation of both groups.[5] However, in both cases the proton stripped from the nitrogen is dispersed through a histidine–aspartate proton relay system and released into the surrounding matrix.[17]
Role in gene regulation
Depending on the site and symmetry of methylation, methylated arginines are considered activating (histone H4R3me2a, H3R2me2s, H3R17me2a, H3R26me2a) or repressive (H3R2me2a, H3R8me2a, H3R8me2s, H4R3me2s) histone marks.[15] Generally, the effect of a histone methyltransferase on gene expression strongly depends on which histone residue it methylates. See Histone#Chromatin regulation.
Disease relevance
Abnormal expression or activity of methylation-regulating enzymes has been noted in some types of human cancers, suggesting associations between histone methylation and malignant transformation of cells or formation of tumors.[18] In recent years, epigenetic modification of the histone proteins, especially the methylation of the histone H3, in cancer development has been an area of emerging research. It is now generally accepted that in addition to genetic aberrations, cancer can be initiated by epigenetic changes in which gene expression is altered without genomic abnormalities. These epigenetic changes include loss or gain of methylations in both DNA and histone proteins.[18]
There is not yet compelling evidence that suggests cancers develop purely by abnormalities in histone methylation or its signaling pathways, however they may be a contributing factor. For example, down-regulation of methylation of lysine 9 on histone 3 (H3K9me3) has been observed in several types of human cancer (such as colorectal cancer, ovarian cancer, and lung cancer), which arise from either the deficiency of H3K9 methyltransferases or elevated activity or expression of H3K9 demethylases.[18][19][20]
DNA repair
The methylation of histone lysine has an important role in choosing the pathway for repairing DNA double-strand breaks.[21] As an example, tri-methylated H3K36 is required for homologous recombinational repair, while dimethylated H4K20 can recruit the 53BP1 protein for repair by the pathway of non-homologous end joining.
Further research
Histone methyltransferase may be able to be used as biomarkers for the diagnosis and prognosis of cancers. Additionally, many questions still remain about the function and regulation of histone methyltransferases in malignant transformation of cells, carcinogenesis of the tissue, and tumorigenesis.[18]
See also
- Histone-Modifying Enzymes
- Histone acetyltransferase (HAT)
- Histone deacetylase (HDAC)
- RNA polymerase control by chromatin structure
- Histone methylation
References
- ^ PMID 14969729.
- ^ PMID 20920745.
- S2CID 17263035.
- PMID 12080090.
- ^ PMID 11413150.
- ^ S2CID 11575783.
- ^ PMID 10899106.
- ^ "Chromatin Network". Retrieved 1 March 2012.
- ^ PMID 17320507.
- PMID 12372303.
- PMID 12628190.
- PMID 10381882.
- PMID 8647869.
- PMID 10652296.
- ^ PMID 28061334.
- PMID 11461695.
- PMID 4689953.
- ^ ISBN 978-0-12-375709-8.
- PMID 15723344.
- S2CID 13456531.
- PMID 29937925.
Further reading
- Trievel RC (2004). "Structure and function of histone methyltransferases". Crit. Rev. Eukaryot. Gene Expr. 14 (3): 147–69. PMID 15248813.
- Conde F, Refolio E, Cordón-Preciado V, Cortés-Ledesma F, Aragón L, Aguilera A, San-Segundo PA (June 2009). "The Dot1 histone methyltransferase and the Rad9 checkpoint adaptor contribute to cohesin-dependent double-strand break repair by sister chromatid recombination in Saccharomyces cerevisiae". Genetics. 182 (2): 437–46. PMID 19332880.
External links
- GeneReviews/NCBI/NIH/UW entry on Kleefstra Syndrome
- Histone-Lysine+N-Methyltransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Protein-Arginine+N-Methyltransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
