A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich's ataxia.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34919435.
- Also identified by DOI 10.1126/sciadv.abj9889 and PMC identifier 8682991.
- Licence recorded as CC BY-NC.
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Abstract
Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. A source of damage to Fe-S clusters is cuprous (Cu<sup>1+</sup>) ions. Since histone H3 enzymatically produces Cu<sup>1+</sup> for copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3–mediated Cu<sup>1+</sup> toxicity is a major determinant of cellular functional pool of Fe-S clusters. Inadequate Fe-S cluster supply, due to diminished assembly as occurs in Friedreich’s ataxia or defective distribution, causes severe metabolic and growth defects in <i>Saccharomyces cerevisiae</i>. Decreasing Cu<sup>1+</sup> abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster–dependent metabolism and growth. Our findings reveal an interplay between chromatin and mitochondria in Fe-S cluster homeostasis and a potential pathogenic role for histone enzyme activity and Cu<sup>1+</sup> in diseases with Fe-S cluster dysfunction.