fig1

Figure 1. Illustration of genotoxic stress-induced NF-κB signaling cascades. In response to genotoxic treatments, NEMO translocated into nucleus could be SUMOylated by PIASy, which enhances the nuclear accumulation of NEMO. The SUMOylation of NEMO may be facilitated by PARP-1/Sam68 and/or PIDD/RIP complex. Nuclear accumulated NEMO can further form a complex with ATM that phosphorylates NEMO and promotes NEMO monoubiqutination. Monoubiquitinated NEMO then exports into cytoplasm along with ATM, where they form a complex with ELKS. ATM-promoted ELKS ubiquitination with K63 chains recruits LUBAC complex, which facilitates the assembly of linear ubiquitin chain attached on NEMO. The ELKS/NEMO anchored ubiquitin chains stabilize binding of TAK1 and IKK complex thereby promoting their activation. ATM may also export into cytoplasm and form a complex with TRAF6, which leads to TRAF6 polyubiquitination. The polyubiquitin chains attached on TRAF6 could also enhance IKK activation. Activated IKK then phosphorylates IκBα and frees NF-κB for nuclear translocation. In the nucleus, NF-κB could drive transactivation of anti-apoptotic genes (e.g. Bcl-xL, XIAP and Survivin), inflammatory cytokines (e.g. IL-6 and IL-8) and oncogenic miRNAs (e.g. miR-21 and miR-181a), resulting in therapeutic resistance and aggressive metastasis in cancer cells. NF-κB: nuclear factor kappa B; PIASy: protein inhibitor of activated; PARP-1: poly (ADP-ribose) polymerase 1; PIDD: p53-induced death domain protein; RIP: receptor interacting protein; TAK1: TGF-beta activated kinase; IKK: IκB kinase 1; TRAF6: TNF receptor-associated factor 6