Disruption of the histone H3 cupric reductase activity prevents global transcriptional rewiring when YFH1 is diminished

Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. An underappreciated source of damage to Fe-S clusters are cuprous (Cu1+) ions. Since histone H3 enzymatically produces Cu1+ to support copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3-mediated Cu1+ toxicity is a major determinant of cellular Fe-S cluster quotient in the budding yeast. Inadequate Fe-S cluster supply, due to diminished assembly as occurs in Friedreich's Ataxia, causes substantial growth defects and numerous transcriptional responses. Decreasing Cu1+ abundance, through attenuation of histone cupric reductase activity via the H3H113N mutation, prevented the widespread transcriptional rewiring. Our findings reveal a novel interplay between chromatin and mitochondria in Fe-S cluster homeostasis. Overall design: mRNA profiles of yeast with the histone H3 H113N mutation and/or YFH1 shutoff grown in fermentative medium

铁硫（Fe-S）簇作为一类广泛蛋白质的必需辅助因子，其功能紊乱会引发广泛的细胞缺陷，最终导致人类疾病。此前未被充分重视的Fe-S簇损伤诱因之一是亚铜（Cu⁺）离子。由于组蛋白H3可通过酶促反应生成亚铜离子以支持铜依赖性功能，我们探究了该活性是否会对Fe-S簇产生有害影响。本研究证实，在出芽酵母中，组蛋白H3介导的亚铜离子毒性是决定细胞内Fe-S簇水平的核心因素。如同弗里德赖希共济失调（Friedreich's Ataxia）中的病变机制，当Fe-S簇组装效率降低时，会导致Fe-S簇供应不足，进而引发严重的生长缺陷与广泛的转录应答。通过H3H113N突变削弱组蛋白铜还原酶活性，进而降低亚铜离子丰度，可阻断这种广泛的转录重编程。本研究结果揭示了染色质与线粒体之间在Fe-S簇稳态调控中的全新相互作用机制。实验设计：对在发酵培养基中培养的、携带组蛋白H3 H113N突变和/或YFH1基因沉默的酵母进行mRNA转录组分析。