The RelA subunits of NF-κB undergo various posttranslational modifications that create specific marks to recruit different effectors to control NF-κB’s temporal and spatial activation [118]. RelA is subject to monomethylation by lysine methyltransferase Set9 (also called Set7 or KMT7) at Lys314/315 in vitro and in vivo in response to stimuli [25]. RelA methylation at these two residues negatively regulates NF-κB function by triggering the ubiquitination and proteasome-mediated degradation of promoter-associated RelA. RelA methylation also serves as a “death” signal for the destruction of DNA-bound, activated NF-κB [25]. Because RelA subunit methylation negatively impacts NF-κB function, designing a molecule that activates Set9 function could potentiate NF-κB inhibition.
