Search
N-lysine methyltransferase SETD8; H4-K20-HMTase SETD8; histone-lysine N-methyltransferase SETD8; lysine N-methyltransferase 5A; PR/SET domain-containing protein 07; PR-Set7; PR/SET07; SET domain-containing protein 8 (SETD8, KMT5A, PRSET7, SET07, SET8)
Function:
- protein-lysine N-methyltransferase
- monomethylates both histones & non-histone proteins
- specifically monomethylates Lys-20 of histone H4 (H4K20me1)
- H4K20me1 is enriched during mitosis & represents a specific tag for epigenetic transcriptional repression
- mainly functions in euchromatin regions, thus playing a role in silencing of euchromatic genes
- required for cell proliferation, probably by contributing to maintenance of proper higher order structure of DNA during mitosis
- involved in chromosome condensation & proper cytokinesis
- nucleosomes are preferred as substrate compared to free histones
- mediates monomethylation of p53/TP53 at Lys-382, leading to repress p53/TP53-target genes
- interacts with L3MBTL1
- inhibition of SETD8 alone is sufficient to trigger replicative senescence in fibroblasts [2]
S-adenosyl-L-methionine + L-lysine-[histone] = S-adenosyl-L-homocysteine + N(6)-methyl-L-lysine-[histone]
Structure:
- although the SET domain contains the active site, both sequences upstream & downstream of the SET domain are required for methyltransferase activity
- belongs to the histone-lysine methyltransferase family, PR/SET subfamily
- contains 1 SET domain
Compartment:
- nucleus, chromosome
- specifically localizes to mitotic chromosomes
- associates with silent chromatin on euchromatic arms
- not associated with constitutive heterochromatin
Alternative splicing: named isoforms=2
Expression:
- not detected during G1 phase
- first detected during S through G2 phases, & peaks during mitosis (at protein level)
- induced by HCFC1 C-terminal chain, independently of HCFC1 N- terminal chain
- SETD8 decreases markedly in senescent fibroblasts [2]
Note:
- uncertain whether Met-1 or Met-72 is the initiator
General
nuclear protein
N-methyltransferase
phosphoprotein
SET domain-containing protein
Properties
SIZE: entity length = 393 aa
MW = 43 kD
COMPARTMENT: cell nucleus
MOTIF: alanine-rich region {6-67}
MOTIF: alanine residue (SEVERAL)
arginine-rich region {29-32}
MOTIF: arginine residue (SEVERAL)
Ser phosphorylation site {S100}
coiled coil {134-163}
SET domain {256-382}
MOTIF: S-adenosyl-L-methionine binding {267-269}
binding site
SITE: 312-312
FOR-BINDING-OF: S-adenosylmethionine
S-adenosyl-L-methionine binding {339-340}
Database Correlations
OMIM 607240
UniProt Q9NQR1
Pfam PF00856
Entrez Gene 387893
Kegg hsa:387893
ENZYME correlations
References
- UniProt :accession Q9NQR1
- Kumamoto University
Cellular senescence prevented by the SETD8 enzyme
Science Daily. March 8, 2017
https://www.sciencedaily.com/releases/2017/03/170308092443.htm
- Tanaka H, Takebayashi S, Sakamoto A et al
The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to
Prevent Senescence-Associated Metabolic Remodeling.
Cell Reports, 2017; 18 (9): 2148
PMID: 28249161 Free Article