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