Johnson Adam J, Veljanoski Filip, O'Doherty Patrick J, Zaman Mohammad S, Petersingham Gayani, Bailey Trevor D, Münch Gerald, Kersaitis Cindy, Wu Ming J
School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.
Department of Pharmacology, School of Medicine and Molecular Medicine Research Group, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.
Metallomics. 2016 May 1;8(5):542-50. doi: 10.1039/c6mt00039h.
Chromium toxicity is increasingly relevant to living organisms such as humans, due to the environmental contamination of chromium and the application of stainless steel-based medical devices like hip prostheses. Despite the investigations in past years, the molecular details for chromium toxicity remain to be delineated. In this study, we seek to gain insights into the molecular aspects of chromium toxicity by screening a genome-wide deletion set of individual genes in Saccharomyces cerevisiae against hexavalent chromium [Cr(vi)] using chromium trioxide. From the primary data collected in this study, two lists of deletion mutants in response to Cr(vi) exposure were obtained, one for the sensitive phenotype and the other for the resistant phenotype. The functional analysis of the genes corresponding to the sensitive mutants reveals the key features of Cr(vi) toxicity, which include genotoxicity, protein damage, disruption of energy and sulfur metabolisms. DNA repair, ubiquitination-mediated protein degradation, iron homeostasis and growth attenuation are the intrinsic facets of the cell's detoxification mechanisms. Protein kinase CK2 is, for the first time, found to be involved in regulating chromium toxicity by reducing the uptake of Cr(vi). Taken together, the findings provide meaningful details into the basic understanding of chromium toxicity in terms of its uptake, modes of action, cellular detoxification and molecular regulatory mechanisms.
由于铬的环境污染以及诸如髋关节假体等不锈钢基医疗器械的应用，铬毒性与人类等生物体的相关性日益增加。尽管过去几年进行了相关研究，但铬毒性的分子细节仍有待阐明。在本研究中，我们试图通过使用三氧化铬针对六价铬[Cr(VI)]筛选酿酒酵母中单个基因的全基因组缺失集，来深入了解铬毒性的分子层面。从本研究收集的原始数据中，获得了两份响应Cr(VI)暴露的缺失突变体列表，一份针对敏感表型，另一份针对抗性表型。对与敏感突变体对应的基因进行功能分析，揭示了Cr(VI)毒性的关键特征，包括遗传毒性、蛋白质损伤、能量和硫代谢的破坏。DNA修复、泛素化介导的蛋白质降解、铁稳态和生长衰减是细胞解毒机制的内在方面。首次发现蛋白激酶CK2通过减少Cr(VI)的摄取参与调节铬毒性。综上所述，这些发现为从铬的摄取、作用模式、细胞解毒和分子调控机制等方面深入理解铬毒性提供了有意义的细节。
