Li Xiaoling, Cao Guanghui, Liu Xiaokang, Tang Tie-Shan, Guo Caixia, Liu Hongmei
Nano-Biotechnology Key Lab of Hebei Province, Yanshan University, Qinhuangdao, China.
State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
Front Cell Neurosci. 2022 Jun 30;16:852002. doi: 10.3389/fncel.2022.852002. eCollection 2022.
Most of the neurodegenerative diseases and aging are associated with reactive oxygen species (ROS) or other intracellular damaging agents that challenge the genome integrity of the neurons. As most of the mature neurons stay in G0/G1 phase, replication-uncoupled DNA repair pathways including BER, NER, SSBR, and NHEJ, are pivotal, efficient, and economic mechanisms to maintain genomic stability without reactivating cell cycle. In these progresses, polymerases are prominent, not only because they are responsible for both sensing and repairing damages, but also for their more diversified roles depending on the cell cycle phase and damage types. In this review, we summarized recent knowledge on the structural and biochemical properties of distinct polymerases, including DNA and RNA polymerases, which are known to be expressed and active in nervous system; the biological relevance of these polymerases and their interactors with neuronal degeneration would be most graphically illustrated by the neurological abnormalities observed in patients with hereditary diseases associated with defects in DNA repair; furthermore, the vicious cycle of the trinucleotide repeat (TNR) and impaired DNA repair pathway is also discussed. Unraveling the mechanisms and contextual basis of the role of the polymerases in DNA damage response and repair will promote our understanding about how long-lived postmitotic cells cope with DNA lesions, and why disrupted DNA repair contributes to disease origin, despite the diversity of mutations in genes. This knowledge may lead to new insight into the development of targeted intervention for neurodegenerative diseases.
大多数神经退行性疾病和衰老都与活性氧（ROS）或其他细胞内损伤因子有关，这些因子会挑战神经元的基因组完整性。由于大多数成熟神经元处于G0/G1期，包括碱基切除修复（BER）、核苷酸切除修复（NER）、单链断裂修复（SSBR）和非同源末端连接（NHEJ）在内的与复制解偶联的DNA修复途径，是在不重新激活细胞周期的情况下维持基因组稳定性的关键、高效且经济的机制。在这些过程中，聚合酶非常突出，这不仅是因为它们负责感知和修复损伤，还因为它们根据细胞周期阶段和损伤类型发挥着更多样化的作用。在这篇综述中，我们总结了关于不同聚合酶的结构和生化特性的最新知识，包括已知在神经系统中表达并具有活性的DNA和RNA聚合酶；这些聚合酶及其与神经元变性的相互作用因子的生物学相关性，将通过与DNA修复缺陷相关的遗传性疾病患者中观察到的神经学异常得到最生动的说明；此外，还讨论了三核苷酸重复（TNR）和受损的DNA修复途径的恶性循环。阐明聚合酶在DNA损伤反应和修复中的作用机制及背景基础，将促进我们对有丝分裂后长寿细胞如何应对DNA损伤，以及尽管基因存在多种突变，但DNA修复功能紊乱为何会导致疾病发生的理解。这些知识可能会为神经退行性疾病的靶向干预发展带来新的见解。
