Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
Apoptosis. 2010 Nov;15(11):1371-81. doi: 10.1007/s10495-010-0501-0.
The DNA damage response (DDR) is a key factor in the maintenance of genome stability. As such, it is a central axis in sustaining cellular homeostasis in a variety of contexts: development, growth, differentiation, and maintenance of the normal life cycle of the cell. It is now clear that diverse mechanisms encompassing cell cycle regulation, repair pathways, many aspects of cellular metabolism, and cell death are inter-linked and act in concert in response to DNA damage. Defects in the DDR in proliferating cells can lead to cancer, while DDR defects in neurons may result in neurodegeneration. Mature neurons are highly differentiated, post-mitotic cells that cannot be replenished after disease or trauma. Their high metabolic activity generates large amounts of reactive oxygen species with DNA damaging capacity. Moreover, their intense transcriptional activity increases the potential for genomic DNA damage. Respectively, neurons have elaborate mechanisms to defend the integrity of their genome, thus ensuring their longevity and functionality in the face of these threats. Over the course of the past two decades, there has been a substantial increase in our understanding of the role of glial cells in supporting the neuronal cell DDR and longevity. This review article focuses on the potential role of the DDR in the etiology and pathogenesis of neurodegenerative diseases, and in addition, it describes various aspects of glial cell functionality in two genomic instability disorders: ataxia telangiectasia (A-T) and Nijmegen breakage syndrome.
DNA 损伤反应（DDR）是维持基因组稳定性的关键因素。因此，它是在各种情况下维持细胞内稳态的中心轴：发育、生长、分化和维持细胞正常生命周期。现在很清楚，包括细胞周期调控、修复途径、细胞代谢的许多方面和细胞死亡在内的多种机制相互关联，并协同作用以应对 DNA 损伤。增殖细胞中 DDR 的缺陷可导致癌症，而神经元中的 DDR 缺陷可能导致神经退行性变。成熟神经元是高度分化的、有丝分裂后的细胞，在疾病或创伤后无法补充。它们的高代谢活性会产生大量具有 DNA 损伤能力的活性氧。此外，它们强烈的转录活性增加了基因组 DNA 损伤的可能性。相应地，神经元有精细的机制来保护其基因组的完整性，从而确保它们在面对这些威胁时的长寿和功能。在过去的二十年中，我们对神经胶质细胞在支持神经元 DDR 和寿命方面的作用有了实质性的了解。本文综述了 DDR 在神经退行性疾病发病机制中的潜在作用，并描述了两种基因组不稳定性疾病：共济失调毛细血管扩张症（A-T）和 Nijmegen 断裂综合征中神经胶质细胞功能的各个方面。
