N-lysine methyltransferase KMT5A (SETD8) (SETD8)

N-lysine methyltransferase KMT5A (SETD8) is the sole enzyme responsible for the monomethylation of histone H4 at lysine 20 (H4K20me1) in mammals, a modification essential for chromatin structure and genome stability [2, 8, 9]. It plays a pivotal role in the cell cycle, with its levels peaking during G2/M and early G1 phases to facilitate chromosome condensation and DNA replication [2, 5, 6]. Beyond its epigenetic role, SETD8 methylates non-histone proteins like p53 and PCNA, which suppresses p53-mediated apoptosis and enhances cell proliferation [2, 4, 6]. SETD8 is frequently overexpressed in various malignancies, including multiple myeloma, glioblastoma, and lung cancer, where it correlates with poor prognosis and drug resistance [1, 3, 12]. Small-molecule inhibitors such as UNC0379 have been developed to target its catalytic activity, leading to H4K20me1 depletion, DNA damage, and cell cycle arrest in cancer cells [1, 9, 13]. These inhibitors show potential for therapeutic intervention, particularly in combination with DNA-damaging agents, by exploiting the target's role in DNA repair and survival pathways [1, 3, 7].

Other names

SET8PR-Set7KMT5APR/SET domain-containing protein 07H4-K20-HMTase KMT5AHistone-lysine N-methyltransferase KMT5ALysine-specific methylase 5ASET domain-containing protein 8

Inhibition of methyltransferase activity through substrate-competitive or covalent binding, resulting in the depletion of H4K20me1, induction of DNA damage, and activation of cell cycle checkpoints or p53-mediated apoptosis [1, 2, 9].