The molecular and genetic dissection of DNA damage response using cellular and animal models

• Antragsteller: Professor Dr. Zhao-Qi Wang
• Fachliche Zuordnung: Zellbiologie
• Förderung: Förderung von 2007 bis 2012
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 54227695

Mutations of key components in the DNA damage response pathways, such as ATM, ATR, MRE11 and NBS1, cause Ataxia-Telangiectasia (A-T), Seckel Syndrome, A-T Like Disorder (A-TLD) and Nijmegen Breakage Syndrome (NBS), respectively. The major symptoms overlap in these diseases ranging from ataxia, microcephaly, immunodeficiency, chromosomal instability and cancer susceptibility. In response to DNA double strand breaks (DSBs), NBS1 recruits, by its C-terminus, ATM to DNA breaks and activates ATM, which in turn phosphorylates NBS1 and other downstream targets. NBS1 seems also to interact with ATR upon replication fork stalls. The interaction of NBS1, ATM and ATR is thus proposed to play a vital role in DNA damage signalling, DNA repair, checkpoints and apoptosis. However, the biological significance of such interactions in pathogenesis of these human diseases remains elusive, due to the fact that null mutation in the MRN complex (NBS1/MRE11/RAD50) or in ATR causes cell and mice lethality. In this project we propose to study: 1. The biological functions of the C-terminus of NBS1 in the pathogenesis of NBS, A-T and A-TLD; 2. The distinct and interdependent functions of ATM and ATR that are regulated by NBS1; and 3. The role of the DSB repair pathways in pathological development. We will take the following approaches: (i) Generation and characterization of mice carrying mutant Nbs1 that lacks Atm interaction domain and of conditional Atr knockout mice to study the role of Atm and Atr activation in lymphoid and neuronal organs; (ii) Construction of an inducible repair assay in mice to test the role of Nbs1, Atm or Atr in DSB repair pathways in vivo. This study is very important, not only for the understanding of the mechanisms responsible for A-T, A-TLD, Seckel and NBS, but also for delineating the network of DNA damage response in vivo. Such knowledge, still lacking today, may facilitate the development of novel strategies for the treatment of neurodegenerative components and the malignancy of these diseas.

• DFG-Verfahren: Sachbeihilfen