Set7/9 is a regulator of ROS-induced NFkB and FOXO3 signaling pathways. (a) Set7/9 may act both as an activator (green) or a suppressor (red) of NFkB in ROS response. Set7/9 augments the expression level of RelA via K37 methylation thereby promoting transactivation of NFkB target genes. On the contrary, Set7/9-mediated methylation of RelA on K314/K315 inhibits its binding to the promoter regions of target genes; (b) Set7/9 positively regulates transcription activity of FOXO3 by methylating it on K271. Furthermore, Set7/9-dependent methylation of FOXO3 on K270 prevents the activation of pro-apoptotic Bim. In addition, Set7/9 upregulates the activity of E2F1 that in turn suppresses FOXO3 activity and mediates Sirt1 methylation on lysine residues 233, 235, 236 and 238 resulting in Sirt1 inhibition of its deacetylation activity. The latter prevents Sirt1-mediated activation of FOXO3.