Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, United States.
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, United States; Department of Developmental Biology, Stanford University, Stanford, CA 94305, United States.
DNA Repair (Amst). 2018 Nov;71:23-32. doi: 10.1016/j.dnarep.2018.08.004. Epub 2018 Aug 23.
From bacteria to humans, ancient stress responses enable organisms to contend with damage to both the genome and the proteome. These pathways have long been viewed as fundamentally separate responses. Yet recent discoveries from multiple fields have revealed surprising links between the two. Many DNA-damaging agents also target proteins, and mutagenesis induced by DNA damage produces variant proteins that are prone to misfolding, degradation, and aggregation. Likewise, recent studies have observed pervasive engagement of a p53-mediated response, and other factors linked to maintenance of genomic integrity, in response to misfolded protein stress. Perhaps most remarkably, protein aggregation and self-assembly has now been observed in multiple proteins that regulate the DNA damage response. The importance of these connections is highlighted by disease models of both cancer and neurodegeneration, in which compromised DNA repair machinery leads to profound defects in protein quality control, and vice versa.
从细菌到人类，古老的应激反应使生物能够应对基因组和蛋白质组的损伤。这些途径长期以来被视为基本独立的反应。然而，来自多个领域的最新发现揭示了两者之间令人惊讶的联系。许多破坏 DNA 的试剂也靶向蛋白质，而 DNA 损伤诱导的突变会产生易错误折叠、降解和聚集的变异蛋白质。同样，最近的研究观察到 p53 介导的反应以及与维持基因组完整性相关的其他因素广泛参与应对错误折叠的蛋白质应激。也许最引人注目的是，调节 DNA 损伤反应的多种蛋白质中现在已经观察到蛋白质聚集和自组装。在癌症和神经退行性疾病的疾病模型中，这些联系的重要性得到了强调，在这些模型中，受损的 DNA 修复机制导致蛋白质质量控制的严重缺陷，反之亦然。
