{"doi":"10.1101/2020.05.29.124032","title":"Reduced Gene Dosage of Histone H4 Prevents CENP-A Mislocalization in <i>Saccharomyces cerevisiae</i>","abstract":"ABSTRACT Mislocalization of the centromeric histone H3 variant (Cse4 in budding yeast, CID in flies, CENP-A in humans) to non-centromeric regions contributes to chromosomal instability (CIN) in yeast, fly, and human cells. Overexpression and mislocalization of CENP-A has been observed in cancers, however, the mechanisms that facilitate the mislocalization of overexpressed CENP-A have not been fully explored. Defects in ubiquitin-mediated proteolysis of overexpressed Cse4 ( GALCSE4 ) leads to its mislocalization and synthetic dosage lethality (SDL) in mutants for E3 ubiquitin ligases (Psh1, Slx5, SCF Met30 , SCF Cdc4 ), Doa1, Hir2, and Cdc7. In contrast, defects in sumoylation of GALcse4K215/216/A/R prevent its mislocalization and do not cause SDL in a psh1 Δ strain. Here, we used a genome-wide screen to identify factors that facilitate the mislocalization of overexpressed Cse4 by characterizing suppressors of the psh1 Δ GALCSE4 SDL. Deletions of histone H4 alleles ( HHF1 or HHF 2), which were among the most prominent suppressors, also suppress slx5Δ, cdc4-1, doa1Δ, hir2Δ , and cdc7-4 GALCSE4 SDL. Reduced dosage of H4 contributes to defects in sumoylation and reduced mislocalization of overexpressed Cse4. We determined that the hhf1-20, cse4-102 , and cse4-111 mutants, which are defective in the Cse4-H4 interaction, also exhibit reduced sumoylation of Cse4 and do not display psh1 Δ GALCSE4 SDL. In summary, we have identified genes that contribute to the mislocalization of overexpressed Cse4 and defined a role for the gene dosage of H4 in facilitating Cse4 sumoylation and mislocalization to non-centromeric regions, contributing to SDL when Cse4 is overexpressed in mutant strains.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126735,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":575239,"name":"Kentaro Ohkuni","orcid":null,"position":1,"is_corresponding":false},{"id":381887,"name":"Wei-Chun Au","orcid":null,"position":2,"is_corresponding":false},{"id":575240,"name":"Olivia Preston","orcid":null,"position":3,"is_corresponding":false},{"id":575241,"name":"Evelyn Suva","orcid":null,"position":4,"is_corresponding":false},{"id":94092,"name":"Michael Costanzo","orcid":"0000-0002-7906-2604","position":5,"is_corresponding":false},{"id":94094,"name":"Charles Boone","orcid":"0000-0002-3542-6760","position":6,"is_corresponding":false},{"id":380263,"name":"Munira A. Basrai","orcid":"0000-0003-0628-8052","position":7,"is_corresponding":false},{"id":380255,"name":"Jessica R. Eisenstatt","orcid":"0000-0003-1562-0408","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-18T23:15:27.226519Z","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":[]}