N-lysine methyltransferase SETD8 (SETD8) (SETD8)

SETD8 (also known as SET8, PR-Set7, or KMT5A) is the sole mammalian lysine methyltransferase responsible for the monomethylation of histone H4 at lysine 20 (H4K20me1) [1, 8]. This epigenetic mark is essential for chromatin compaction, DNA replication, and the recruitment of DNA repair factors like 53BP1 to double-strand breaks [1, 11, 15]. Beyond histones, SETD8 also methylates non-histone proteins such as p53, PCNA, and Numb, thereby modulating their stability and function [1, 5, 10]. In many cancers, SETD8 is overexpressed, where it promotes cell proliferation, suppresses p53-mediated apoptosis, and enhances genomic stability in malignant cells [6, 9, 14]. Consequently, SETD8 has emerged as a promising therapeutic target, with small-molecule inhibitors like UNC0379 demonstrating the ability to induce cell cycle arrest and apoptosis in various tumor models [2, 6, 14]. Therapeutic challenges include ensuring selectivity over other SET-domain methyltransferases and managing potential toxicities related to its fundamental role in the cell cycle and DNA damage response [1, 13].

Other names

SET8PR-Set7KMT5ALysine N-methyltransferase 5APR/SET domain-containing protein 7

Lysine methyltransferase inhibition [2, 10]