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

Mre11/Rad50/Nbs1 (MRN) 复合物在中枢神经系统发育和衰老中的作用

• 批准号: 218893643
• 负责人: Dr. Pierre-Olivier Frappart, Ph.D.
• 金额: --
• 依托单位: Institut für Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/218893643?language=en
• 关键词: Role; Mre11; Rad50; Nbs1; MRN

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

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组织的稳定性是遗传信息可靠传递和预防癌症发生的基础。发育中的中枢神经系统（CNS）对DNA损伤尤其是DNA双链断裂（DSB）表现出高度敏感性。在中枢神经系统中，DNA双链断裂引发一系列信号传导事件，导致断裂的修复和解决，或者非常频繁地导致细胞凋亡。此外，DSB修复对中枢神经系统（CNS）的重要性通过在患有与DSB修复缺陷相关的遗传性疾病的患者中观察到的神经异常来说明，所述遗传性疾病例如共济失调-毛细血管扩张（A-T）、共济失调-毛细血管扩张样障碍（A-T）和奈梅亨断裂综合征（NBS）或Seckel综合征。本研究项目的目的是使用小鼠模型分析MRN复合物失活对中枢神经系统正常发育、神经变性和肿瘤发生的后果。本研究将有助于更好地了解CNS对DNA损伤的反应，Mre 11/Rad 50/Nbs 1（MRN）复合物的功能以及三种主要的DNA修复PI-3激酶ATR，ATM和DNA-PKcs在MRN复合物生物学功能中的作用。最终，它将为脑肿瘤和神经退行性疾病的精心治疗提供新的线索