Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Departamento de Biología Molecular, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
EMBO J. 2021 Jul 1;40(13):e103311. doi: 10.15252/embj.2019103311. Epub 2021 May 12.
Due to their capability to transport chemicals or proteins into target cells, cell-penetrating peptides (CPPs) are being developed as therapy delivery tools. However, and despite their interesting properties, arginine-rich CPPs often show toxicity for reasons that remain poorly understood. Using a (PR)n dipeptide repeat that has been linked to amyotrophic lateral sclerosis (ALS) as a model of an arginine-rich CPP, we here show that the presence of (PR)n leads to a generalized displacement of RNA- and DNA-binding proteins from chromatin and mRNA. Accordingly, any reaction involving nucleic acids, such as RNA transcription, translation, splicing and degradation, or DNA replication and repair, is impaired by the presence of the CPPs. Interestingly, the effects of (PR)n are fully mimicked by protamine, a small arginine-rich protein that displaces histones from chromatin during spermatogenesis. We propose that widespread coating of nucleic acids and consequent displacement of RNA- and DNA-binding factors from chromatin and mRNA accounts for the toxicity of arginine-rich CPPs, including those that have been recently associated with the onset of ALS.
由于其能够将化学物质或蛋白质输送到靶细胞，细胞穿透肽（CPP）正被开发为治疗药物输送工具。然而，尽管具有有趣的特性，但富含精氨酸的 CPP 通常表现出毒性，其原因仍知之甚少。我们使用与肌萎缩侧索硬化症（ALS）相关的（PR）n 二肽重复作为富含精氨酸的 CPP 的模型，表明（PR）n 的存在导致 RNA 和 DNA 结合蛋白从染色质和 mRNA 中普遍移位。因此，任何涉及核酸的反应，如 RNA 转录、翻译、剪接和降解，或 DNA 复制和修复，都会受到 CPP 的影响。有趣的是，（PR）n 的作用完全被鱼精蛋白模拟，鱼精蛋白是一种富含精氨酸的小蛋白，在精子发生过程中从染色质中取代组蛋白。我们提出，核酸的广泛覆盖以及 RNA 和 DNA 结合因子从染色质和 mRNA 中的移位，解释了富含精氨酸的 CPP 的毒性，包括最近与 ALS 发病相关的 CPP。
