IKK3 and DNA Damage Response Mechanisms

IKK3 is a kinase involved in antiviral responses and is also known for its role in cellular stress signaling. Beyond its well-documented function, IKK3 contributes to cell survival under genotoxic stress by regulating nuclear signaling pathways.
IKK3 Activation and Nuclear Localization
Upon DNA damage, IKK3 is phosphorylated and translocates into the nucleus. This nuclear retention depends on the phosphorylation of PML, which facilitates IKK3 accumulation in PML nuclear bodies. These compartments act as signaling hubs where IKK3 interacts with regulatory proteins.
SUMOylation and Functional Modification
Inside the PML nuclear bodies, IKK3 associates with TOPORS, an E3 SUMO ligase, which modifies IKK3 by SUMOylation at lysine 231. This modification is required for IKK3 to activate nuclear substrates, including NF-kB p65. Phosphorylation of NF-kB p65 contributes to cellular responses following genotoxic stress.