Oxidative stress and metabolic reconfiguration in the development of diseases with underlying deficiencies in DNA repair.

DNA 修复潜在缺陷的疾病发展中的氧化应激和代谢重构。

• 批准号: 233376861
• 负责人: Professor Dr. Martin J. Digweed
• 金额: --
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/233376861?language=en
• 关键词: Oxidative; stress; metabolic; reconfiguration; development

Our own previous studies indicate that depletion of NAD+ due to hyperactivation of poly(ADP-ribose) polymerase, as a consequence of unrepaired DNA damage, has a profound effect on the redox status of a cell leading to raised levels of reactive oxygen species (ROS). One of the main and most relevant targets of ROS is DNA, leading to DNA damage which may then be fixed as mutations. Cells unable to deal efficiently with DNA damage, such as those with an underlying deficiency in DNA repair enzymes, seemingly have a double challenge: the primary genotoxic insult and the ensuing oxidative stress. One aim of this proposal is to examine the role of poly(ADP-ribose) polymerase hyperactivation and oxidative stress in diseases which are deficient in key players in the repair of DNA double-strand breaks: ATM, NBN, XLF, LIGIV, FANCD1/BRCA2, FANCN/PALB2 etc. The effect of permanent stress due to DNA damage is often compensated for by so called metabolic reconfiguration. For example, after DNA damage, activated ATM promotes the pentose phosphate pathway via glucose-6-phosphate dehydrogenase leading to increased NADPH production and improved antioxidant capacity. In this project we will examine a collection of cell lines from distinct, but overlapping, disorders with deficiencies in the repair of DNA double-strand breaks for changes in genes regulated by antioxidant response elements (ARE) in the expectation that ROS arising as normal endogenous metabolites, for example during mitochondrial respiration, might be the target of metabolic reconfiguration. Polymorphisms in AREs will also be examined, particularly with respect to clinical variation in the DNA repair deficiency Nijmegen Breakage Syndrome (NBS). For this we have over 40 cell lines from clinically well characterised patients, all with the same homozygous founder mutation. For many of these cell lines, the amount of hypomorphic NBN protein fragment has been determined and correlated with clinical course, particularly cancer incidence.

我们自己先前的研究表明，由于未经修复的DNA损伤，聚（ADP-核糖）聚合酶的过度激活导致NAD+的耗竭，对细胞的氧化还原状态产生了深远的影响，导致反应性氧（ROS）的水平升高。 ROS的主要和最相关的靶标之一是DNA，导致DNA损伤，然后可能被固定为突变。无法有效处理DNA损伤的细胞，例如DNA修复酶缺乏潜在缺乏的细胞，似乎有双重挑战：主要的遗传毒性损伤和随之而来的氧化应激。该提案的目的是检查聚（ADP-核糖）聚合酶过度激活和氧化应激在疾病中的作用，这些疾病中的主要参与者缺乏DNA双链断裂的主要参与者：ATM，NBN，NBN，XLF，Ligiv，Ligiv，Ligiv，FANCD1/BRCA2，FANCD1/BRCA2，FANCN/PALB2，FANCN/PALB2等人经常造成的赔偿应应得的DNA损害，而DNA的责任则是DNA的效应。例如，在DNA损伤后，激活的ATM通过葡萄糖-6-磷酸脱氢酶促进五磷酸途径，从而导致NADPH产生增加并提高抗氧化能力。在这个项目中，我们将研究来自不同但重叠的细胞系的集合，在修复DNA双链破裂方面存在缺陷的疾病，以实现由抗氧化剂反应元素（aS）调节的基因变化（例如），例如，在线粒体呼吸中，可能是正常的内源代谢产生的ROS，可能是MITochrial seckiration seckiration sepration sepration sepration sepiration of Mitochrial sepration of Metiration remotiration of Meterabolation of Meterabolation的目标。还将检查ARES中的多态性，特别是在DNA修复缺乏型Nijmegen Breakage综合征（NBS）的临床变异方面。为此，我们有来自临床表征良好的患者的40多个细胞系，所有患者均具有相同的纯合创始人突变。对于许多这样的细胞系，已经确定并与临床病程（尤其是癌症的发生率）确定并相关的肌肉NBN蛋白片段的量。