Oxidative DNA Damage And Its Processing

氧化损伤主要通过碱基切除修复(BER)途径从DNA中移除。BER是通过四个酶步骤进行的，但现在很清楚，其他几种蛋白质通过蛋白质-蛋白质相互作用来调节BER效率。我们和其他人确定了核心BER酶的几种蛋白质相互作用。氧化DNA损伤与大脑老化、神经退行性疾病和神经系统疾病有关。损伤可能是由正常的细胞代谢造成的，这种代谢随着年龄的增长而积累，或者是由急性细胞应激条件造成的突发性氧化损伤。脑细胞具有特别高的基础代谢活动水平，并使用不同的氧化损伤修复机制来消除DNA和dNTP池中的氧化损伤。在功能性DNA修复反应的背景下，这种损伤的积累与正常衰老有关，但脑细胞修复缺陷可能导致神经功能障碍。增殖细胞对BER的需求也与DNA损伤后神经发生中许多BER酶的高水平相关。然而，该途径对于正常的神经维持也是必要的，因为在一些糖基酶缺陷的动物中可以看到缺血性中风后更大的梗塞体积。此外，由于复制聚合酶水平降低，有丝分裂后BER对DNA聚合酶的需求可能比增殖细胞更重要。BER反应可能与许多与氧化应激增加相关的神经退行性疾病的发生和发展特别相关，包括我们正在研究的阿尔茨海默氏症。

Oxidative lesions are removed from DNA primarily via the base excision repair (BER) pathway. BER is carried out through four enzymatic steps, but it is now clear that several other proteins modulate BER efficiency through protein-protein interactions. We and others identified several protein interactions for the core BER enzymes. Oxidative DNA damage is implicated in brain aging, neurodegeneration and neurological diseases. Damage can be created by normal cellular metabolism, which accumulates with age, or by acute cellular stress conditions which create bursts of oxidative damage. Brain cells have a particularly high basal level of metabolic activity and use distinct oxidative damage repair mechanisms to remove oxidative damage from DNA and dNTP pools. Accumulation of this damage in the background of a functional DNA repair response is associated with normal aging, but defective repair in brain cells can contribute to neurological dysfunction. The requirement for BER in proliferating cells also correlates with high levels of many of the BER enzymes in neurogenesis after DNA damage. However, the pathway is also necessary for normal neural maintenance as larger infarct volumes after ischemic stroke are seen in some glycosylase deficient animals. Further, the requirement for DNA polymerase in post-mitotic BER is potentially more important than in proliferating cells due to reduced levels of replicative polymerases. The BER response may have particular relevance for the onset and progression of many neurodegenerative diseases associated with an increase in oxidative stress including Alzheimer's, which we are pursuing.