Department of Chemical Engineering, Bogazici University, Istanbul, 34342, Turkey.
Division of Cardiovascular Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.
Sci Rep. 2020 Oct 28;10(1):18487. doi: 10.1038/s41598-020-75511-w.
Copper is a crucial trace element for all living systems and any deficiency in copper homeostasis leads to the development of severe diseases in humans. The observation of extensive evolutionary conservation in copper homeostatic systems between human and Saccharomyces cerevisiae made this organism a suitable model organism for elucidating molecular mechanisms of copper transport and homeostasis. In this study, the dynamic transcriptional response of both the reference strain and homozygous deletion mutant strain of CCC2, which encodes a Cu-transporting P-type ATPase, were investigated following the introduction of copper impulse to reach a copper concentration which was shown to improve the respiration capacity of CCC2 deletion mutants. The analysis of data by using different clustering algorithms revealed significantly affected processes and pathways in response to a switch from copper deficient environment to elevated copper levels. Sulfur compound, methionine and cysteine biosynthetic processes were identified as significantly affected processes for the first time in this study. Stress response, cellular response to DNA damage, iron ion homeostasis, ubiquitin dependent proteolysis, autophagy and regulation of macroautophagy, DNA repair and replication, as well as organization of mitochondrial respiratory chain complex IV, mitochondrial organization and translation were identified as significantly affected processes in only CCC2 deleted strain. The integration of the transcriptomic data with regulome revealed the differences in the extensive re-wiring of dynamic transcriptional organization and regulation in these strains.
铜是所有生命系统的关键微量元素，任何铜稳态失衡都会导致人类严重疾病的发生。人类和酿酒酵母的铜稳态系统在进化上广泛保守，这使得该生物成为阐明铜运输和稳态分子机制的合适模式生物。在这项研究中，在引入铜脉冲以达到一种浓度的铜后，研究了参考菌株和编码铜转运 P 型 ATP 酶的 CCC2 纯合缺失突变菌株的动态转录反应，该浓度的铜已被证明可以提高 CCC2 缺失突变体的呼吸能力。使用不同聚类算法对数据进行分析，揭示了在从缺铜环境切换到高铜水平时，受到显著影响的过程和途径。硫化合物、蛋氨酸和半胱氨酸生物合成过程首次被确定为受影响的显著过程。应激反应、细胞对 DNA 损伤的反应、铁离子稳态、泛素依赖性蛋白水解、自噬和巨自噬的调节、DNA 修复和复制，以及线粒体呼吸链复合物 IV 的组织、线粒体组织和翻译，仅在 CCC2 缺失菌株中被确定为受影响的过程。将转录组数据与调控组整合，揭示了这些菌株中动态转录组织和调控的广泛重新布线的差异。
