IKKgModification Triggers NFkB Activation in Response to DNA Damage

DNA-damaging agents belong to the most widely used anti-cancer drugs. Depending on the extent of damage, the cells are either arrested in the cell cycle to allow DNA repair or the cells undergo apoptosis. The tumor suppressor p53 is a primary sensor of genotoxic stress and induces cell-cycle arrest or apoptosis (Vousden 2002). A major obstacle to an efficient anti-cancer therapy is the activation of NF-KB-mediated pro-survival signaling by DNA-damaging agents. There is a complex crosstalk between p53 and NF-kB that involves antagonistic as well as cooperative effects in the induction of apoptosis (Perkins 2007). Owing to its potent anti-apoptotic activity, NF-kB contributes to acquired chemoresistance. Analysis of the exact mechanisms of NF-kB activation after genotoxic stress highlights that distinct signaling complexes are involved in this inside-out (nuclear to cytosolic) pathway.

Atm Kinase Interactions

Fig. 4 Nuclear to cytoplasmic NF-kB signaling in response to genotoxic stress. Genotoxic and cellular stresses initiate the formation of a nuclear protein complex containing PIDD, RIP1, sumoylated IKKy and active ATM. Phosphorylation of IKKy by ATM leads to an exchange of Sumo to mono-ubiquitin on IKKy. Ubiquitinated IKKy and associated ATM are exported to the cytoplasm where the proteins reassemble with the cytoplasmic IKK complex and mediate IKK activation by a so far unknown mechanism. Subsequent nuclear translocation of NF-kB induces a pro-survival gene program

Fig. 4 Nuclear to cytoplasmic NF-kB signaling in response to genotoxic stress. Genotoxic and cellular stresses initiate the formation of a nuclear protein complex containing PIDD, RIP1, sumoylated IKKy and active ATM. Phosphorylation of IKKy by ATM leads to an exchange of Sumo to mono-ubiquitin on IKKy. Ubiquitinated IKKy and associated ATM are exported to the cytoplasm where the proteins reassemble with the cytoplasmic IKK complex and mediate IKK activation by a so far unknown mechanism. Subsequent nuclear translocation of NF-kB induces a pro-survival gene program

Topoisomerase inhibitors etoposide (Eto) or camptothecin (Cpt) exhibit cyto-static effects by inducing DNA double-strand breaks and therefore are potent inducers of NF-kB activity (Fig. 4). The actual sensor of DNA double-stranded breaks is unknown. The primary cellular transducer for DNA damage is the ATM (ataxia telangiectasia mutated) kinase. ATM-deficient cells from patients with the genomic instability ataxia telangiectasia are blocked in NF-kB activation in response genotoxic stress agents, such as y-ionizing radiation (IR) or Cpt (Li et al. 2001; Piret et al. 1999). Upon Eto or Cpt treatment, IKKy enters the nucleus where it associates with PIDD (p53-induced death domain) and RIP1, both proteins having essential functions in the control of NF-kB activation in response to DNA damage (Hur et al. 2003; Janssens and Tschopp 2006). Further, IKKy is retained in the nucleus by site-directed sumoylation mediated by PIASy (protein inhibitor of activated STATy) that acts as the SUMO (small ubiquitin-like modifier) ligase (Mabb et al. 2006; Wu et al. 2006b). However, the exact mechanism for genotoxic-stress-induced nuclear uptake of IKKy, PIDD and RIP1 is unknown. Intriguingly, activated ATM kinase preferentially associates with SUMO-conjugated IKKy. ATM kinase then phosphorylates IKKy, inducing an exchange of SUMO to mono-ubiquitin-conjugated IKKy, which is exported together with ATM kinase from the nucleus (Wu et al. 2006b). In the cytosol, mono-ubiquitinated IKKy promotes assembly of the ATM-IKK complex that induces IkB degradation, nuclear translocation of NF-kB and induction of an anti-apoptotic gene program.

To date, many questions still remain unresolved concerning genotoxic-stress-induced NF-kB activation, such as, e.g.: where is the inducible IKKy-PIDD-RIP1 complex formed, how are these proteins targeted to the nucleus, what is the exact mechanism that mediates the switch from SUMO-IKKy to ubiquitin-IKKy and what is the ubiquitin ligase for IKKy? Further, it is completely unresolved how ATM-IKKy activates cytosolic IKK complex and whether a distinct IKK complex exists for mediating DNA damage responses. However, these novel insights reveal that dynamic protein complexes are required for inducing an anti-apoptotic gene program in response to genotoxic stress. Future studies must determine whether pharmacological inhibitors can be used to selectively interfere with these complexes to identify substances that counteract acquired chemoresistance.

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