Role of the Mre11/Rad50/Nbs1 (MRN) complex in the development and ageing of the Central Nervous System

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The integrity of DNA inside cells is constantly being challenged by endogenous and exogenous DNA-damaging agents. Stability of genomic DNA organization is fundamental to the faithful transmission of genetic information and the prevention of carcinogenesis. The developing central nervous system (CNS) exhibits a high sensitivity to DNA damage and particularly to DNA double-strand breaks (DSBs). In the CNS, DNA DSBs trigger a cascade of signalling events that lead to repair and resolution of the break, or as is very frequent, to apoptosis. Additionally the importance of DSBs repair to the central nervous system (CNS) is illustrated by the neurological abnormalities observed in patients with hereditary diseases associated with defects in DSBs repair such as Ataxia-Telangiectasia (A-T), Ataxia-Telangiectasia Like Disorder (A-TLD) and Nijmegen Breakage Syndrome (NBS) or Seckel syndrome. The objectives of this research project are to analyse the consequences of inactivation of the MRN complex on the normal development, neurodegeneration and tumorigenesis of the central nervous system using mouse models. This study will lead to a better knowledge on the response of CNS to DNA damage, the function of the Mre11/Rad50/Nbs1 (MRN) complex and the respective role of the three main DNA repair PI-3 kinases ATR, ATM and DNA-PKcs in the biological function of the MRN complex. Ultimately, it will provide new clues to elaborate treatments for brain tumours and neurodegenerative diseases