Role of the DNA damage signalling and repair pathways in the prevention of tumorigenesis and neurodegeneration in the central nervous system

细胞内DNA的完整性不断受到内源性和外源性DNA损伤剂的挑战。基因组DNA结构的稳定对于遗传信息的忠实传递和预防癌症的发生具有重要意义。发育中的神经系统对DNA损伤，特别是DNA双链断裂(DSB)表现出高度的敏感性。在神经系统中，DNADSB触发一连串的信号事件，导致断裂的修复和解决，或者非常频繁的细胞凋亡。此外，DSB修复对中枢神经系统(CNS)的重要性通过观察到与DSB修复缺陷相关的遗传病患者的神经异常来说明，如A-T、A-TLD和NBS或Seckel综合征。本研究项目的目的是利用小鼠模型分析DNA损伤修复/信号基因失活对中枢神经系统正常发育和神经变性的影响。该研究项目将专注于参与DNA损伤反应的两个基因SMC1(编码DNA损伤信号蛋白)和Rint-1(编码Rad50相互作用蛋白)。这项研究将使我们能够更好地了解中枢神经系统对DNA损伤的反应。最终，它将为脑瘤和神经退行性疾病的详细治疗提供新的线索。

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 nervous system exhibits a high sensitivity to DNA damage and in particularly to DNA double-strand breaks (DSBs). In nervous system, DNA DSBs trigger a cascade of signalling events that lead to repair and resolution of the break, or as is very frequent, 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 A-T, A-TLD and NBS or Seckel syndrome. The objectives of this research project is to analyse the consequences of inactivation of DNA damage repair/signalling genes on the normal development and neurodegeneration of the central nervous system using mouse models. The research project will be focused on two genes SMC1 (coding for a DNA damage signalling protein) and RINT-1 (coding for a Rad50 interacting protein) that are involved in DNA damage response. This study will allow to acquire a better knowledge about the response of CNS to DNA damage. Ultimately, it will provide new clues to elaborate treatments for brain tumours and neurodegenerative diseases.