Mechanisms of DNA damage induced IKK and NF-kB activation

• Antragsteller: Dr. Michael Hinz; Professor Dr. Claus Scheidereit
• Fachliche Zuordnung: Zellbiologie
• Förderung: Förderung von 2011 bis 2016
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 194679478

Mammalian cells have developed a network of conserved DNA damage response pathways, to en-counter the threats of DNA-damaging agents from endogenous and environmental sources. Sensor proteins like kinase ataxia telangiectasia mutated (ATM) or poly(ADP-ribose)-polymerase-1 (PARP-1), detect DNA lesions and initiate DNA repair and activation of transcription factors such as p53 and NF- κB. While NF-κB triggers cell survival, p53 induces cell-cycle arrest or cell death. ATM and PARP-1 dependent NF-κB activation is characterized by the formation of nuclear and cytoplasmic signaling complexes, which are required for a series of protein modifications, including poly(ADP-ribose) (PAR) formation, IKKγ SUMOylation and monoubiquitination, as well as TRAF6 autoubiquitination. We want to investigate how these specific protein modifications contribute to the DNA damage induced NF-κB pathway and search for further novel components in the signaling cascade. Since p53 as well as NF- κB activation requires PARP-1 and ATM, we propose that a functional crosstalk between both tran-scription factors exist. Thus, we plan to analyze, how the key regulatory components of DNA damage response affect genotoxic stress-induced target gene signatures of NF-κB and p53. The expected outcome will provide a better understanding of resistance to cancer therapy and facilitate the devel-opment of novel anti-cancer agents.

• DFG-Verfahren: Sachbeihilfen