{"doi":"10.1101/2021.06.14.448268","title":"A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich’s Ataxia","abstract":"Abstract 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 (Cu 1+ ) ions. Since histone H3 enzymatically produces Cu 1+ to support copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3-mediated Cu 1+ toxicity is a major determinant of cellular Fe-S cluster quotient. Inadequate Fe-S cluster supply, either due to diminished assembly as occurs in Friedreich’s Ataxia or defective distribution, causes severe metabolic and growth defects in S. cerevisiae . Decreasing Cu 1+ 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 a novel interplay between chromatin and mitochondria in Fe-S cluster homeostasis, and a potential pathogenic role for histone enzyme activity and Cu 1+ in diseases with Fe-S cluster dysfunction. Teaser Reduction of Cu 1+ production by histone H3 restores cellular deficiencies caused by insufficient supply of iron-sulfur clusters.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":224906,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":271905,"name":"Narsis Attar","orcid":"0000-0002-5847-7587","position":1,"is_corresponding":false},{"id":271911,"name":"Nathan V. Mallipeddi","orcid":"0000-0003-2193-5932","position":2,"is_corresponding":false},{"id":271908,"name":"Chen Cheng","orcid":"0000-0002-9610-1345","position":3,"is_corresponding":false},{"id":271907,"name":"Maria Vogelauer","orcid":"0000-0003-1360-0526","position":4,"is_corresponding":false},{"id":271910,"name":"Stefan Schmollinger","orcid":"0000-0002-7487-8014","position":5,"is_corresponding":false},{"id":271917,"name":"Sabeeha Merchant","orcid":"0000-0002-2594-509X","position":6,"is_corresponding":false},{"id":271918,"name":"Siavash K. Kurdistani","orcid":"0000-0003-3295-3511","position":7,"is_corresponding":false},{"id":271906,"name":"Oscar A. Campos","orcid":"0000-0002-5645-7275","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-18T23:54:22.889584Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}