Fig. 4. Regulation of KMT/KDM protein stability in a cell cycle-dependent manner.

Schematic representation of histone lysine methylation modifiers regulated by cell cycle-dependent protein degradation. SET8 is degraded by SCF^Skp2 at the G1/S transition and is dynamically regulated by CRL4^Cdt2 during the S phase in a PCNA-dependent manner. PARP1-mediated poly(ADP-ribosyl)ation of SET8 promotes its UPS-dependent degradation. SET8 is also regulated in a phosphorylation-dependent manner during the G2/M phase by the CDK1/cyclin B complex, while the dephosphorylation of SET8 by CDC14 in the late M phase leads to its degradation by the APC/C^Cdh1 complex. SCF^Fbxl4-dependent proteasomal degradation accounts for the decrease in the KDM4A level in the S phase. PHF8 is regulated by the APC/C^Cdc20 complex in the G2/M phase. MLL1 degradation is mediated by the E3 ligase complex SCF^Skp2 in the S phase of the cell cycle and by the APC/C^Cdc20 complex in the late M phase. In response to genotoxic stress during the S phase, the DNA replication checkpoint kinase ATR phosphorylates MLL1 and inhibits its degradation mediated by SCF^Skp2. The different colors of the histone methylation modifiers indicate specific targets of the modifiers.