Histone-lysine N-methyltransferase KMT5A (SETD8)

Histone-lysine N-methyltransferase KMT5A (SETD8) is a SET domain-containing protein-lysine N-methyltransferase that catalyzes monomethylation of histone H4 at lysine 20 (H4K20me1) and also methylates non-histone proteins including p53 and proliferating cell nuclear antigen (PCNA). It is the only known mammalian enzyme responsible for H4K20 monomethylation in vivo, a key epigenetic mark involved in chromatin compaction, DNA replication origin licensing, DNA damage signaling, and recruitment of repair factors such as 53BP1. SETD8 expression and activity are tightly regulated throughout the cell cycle, peaking in G2/M and early G1 and being largely absent in S phase, and its genetic loss causes defects in cell cycle progression, nuclear condensation, and early embryonic lethality. Dysregulation and overexpression of SETD8 are observed in multiple cancers, where it promotes tumorigenesis partly through monomethylation of p53 (suppressing p53-dependent transcription and apoptosis) and monomethylation of PCNA (stabilizing PCNA and enhancing proliferation), making SETD8 an attractive epigenetic cancer drug target for which selective substrate-competitive inhibitors such as UNC0379 have been developed as tool compounds.

Other names

SETD8SET8PR-Set7PR/SET7N-lysine methyltransferase KMT5AProtein-lysine N-methyltransferase KMT5AHistone H4 lysine 20 methyltransferaseH4K20 methyltransferase

Inhibition of SETD8 catalytic activity, blocking monomethylation of histone H4 Lys20 (H4K20me1); Substrate-competitive inhibition at the H4K20-binding site; SAM/S-adenosyl-L-methionine cofactor-competitive or mixed inhibition in some chemotypes; Reduction of SETD8-dependent methylation of non-histone substrates such as p53 and PCNA, leading to enhanced p53 tumor suppressor activity and reduced PCNA-driven proliferation