GSE176575
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