Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil; Núcleo de Pesquisa em Ciências Biológicas & Departamento de Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, 35400-000 Ouro Preto, MG, Brazil.
Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil; Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine, University of California, San Diego, CA 92093, USA.
Semin Cell Dev Biol. 2021 Jun;114:20-35. doi: 10.1016/j.semcdb.2020.10.009. Epub 2020 Nov 21.
Human genetic syndromes deficient in nucleotide excision repair (NER), such as xeroderma pigmentosum and Cockayne syndrome, may present neurological abnormalities and premature aging symptoms. Unrepaired endogenously generated DNA damage that hampers transcription is a strong candidate that contributes to the development of these severe effects in neuronal tissue. Endogenous lesions include those generated due to byproducts of cellular metabolisms, such as reactive oxygen species. This review presents much of the evidence on the mechanisms related to neurodegenerative processes associated with DNA damage responses. The primary focus is on the effects of the transcription machinery, including the accumulation of DNA•RNA hybrids (R-loops) that, in turn, influence DNA damage and repair metabolism. Moreover, several neuronal tissues present higher expression of long genes, a genomic subset more affected by DNA lesions, which may explain part of the neurological abnormalities in these patients. Also, neuronal tissues have different DNA repair capabilities that might result in different neurological consequences, as observed in patients and NER deficient animal models. The better understanding of how the accumulation of transcription blocking lesions can lead to neurological abnormalities and premature aging-like phenotypes may assist us in finding potential biomarkers and therapeutic targets that might improve the lives of these patients, as well as other neurological disorders in the general population.
人类核苷酸切除修复（NER）缺陷的遗传综合征，如着色性干皮病和 Cockayne 综合征，可能表现出神经异常和早衰症状。未修复的内源性产生的转录受阻的 DNA 损伤是导致神经元组织发生这些严重影响的一个强有力的候选因素。内源性损伤包括由于细胞代谢副产物引起的损伤，如活性氧物种。这篇综述介绍了与 DNA 损伤反应相关的神经退行性过程的机制相关的大量证据。主要重点是转录机制的影响，包括 DNA•RNA 杂交（R 环）的积累，进而影响 DNA 损伤和修复代谢。此外，一些神经元组织中长基因的表达水平较高，这是基因组中受 DNA 损伤影响更大的一部分，这可以解释这些患者中部分神经异常的原因。此外，神经元组织具有不同的 DNA 修复能力，这可能导致不同的神经后果，如在患者和 NER 缺陷动物模型中观察到的那样。更好地了解转录受阻损伤的积累如何导致神经异常和早衰样表型，可能有助于我们找到潜在的生物标志物和治疗靶点，从而改善这些患者以及普通人群中其他神经疾病的生活质量。
