{"doi":"10.1534/g3.120.401131","title":"Dbf4-Dependent Kinase (DDK)-Mediated Proteolysis of CENP-A Prevents Mislocalization of CENP-A in<i>Saccharomyces cerevisiae</i>","abstract":"Abstract The evolutionarily conserved centromeric histone H3 variant (Cse4 in budding yeast, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of CENP-A to non-centromeric chromatin contributes to chromosomal instability (CIN) in yeast, fly, and human cells and CENP-A is highly expressed and mislocalized in cancers. Defining mechanisms that prevent mislocalization of CENP-A is an area of active investigation. Ubiquitin-mediated proteolysis of overexpressed Cse4 (GALCSE4) by E3 ubiquitin ligases such as Psh1 prevents mislocalization of Cse4, and psh1Δ strains display synthetic dosage lethality (SDL) with GALCSE4. We previously performed a genome-wide screen and identified five alleles of CDC7 and DBF4 that encode the Dbf4-dependent kinase (DDK) complex, which regulates DNA replication initiation, among the top twelve hits that displayed SDL with GALCSE4. We determined that cdc7-7 strains exhibit defects in ubiquitin-mediated proteolysis of Cse4 and show mislocalization of Cse4. Mutation of MCM5 (mcm5-bob1) bypasses the requirement of Cdc7 for replication initiation and rescues replication defects in a cdc7-7 strain. We determined that mcm5-bob1 does not rescue the SDL and defects in proteolysis of GALCSE4 in a cdc7-7 strain, suggesting a DNA replication-independent role for Cdc7 in Cse4 proteolysis. The SDL phenotype, defects in ubiquitin-mediated proteolysis, and the mislocalization pattern of Cse4 in a cdc7-7 psh1Δ strain were similar to that of cdc7-7 and psh1Δ strains, suggesting that Cdc7 regulates Cse4 in a pathway that overlaps with Psh1. Our results define a DNA replication initiation-independent role of DDK as a regulator of Psh1-mediated proteolysis of Cse4 to prevent mislocalization of Cse4.","journal":"G3 Genes Genomes Genetics","year":2020,"id":72001,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"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":380256,"name":"Lars Boeckmann","orcid":"0000-0003-0098-6546","position":1,"is_corresponding":false},{"id":381887,"name":"Wei-Chun Au","orcid":null,"position":2,"is_corresponding":false},{"id":380257,"name":"Valérie Garcia","orcid":"0000-0002-4941-0989","position":3,"is_corresponding":false},{"id":381888,"name":"Levi Bursch","orcid":null,"position":4,"is_corresponding":false},{"id":380258,"name":"Josefina Ocampo","orcid":"0000-0002-6745-2525","position":5,"is_corresponding":false},{"id":94092,"name":"Michael Costanzo","orcid":"0000-0002-7906-2604","position":6,"is_corresponding":false},{"id":380259,"name":"Michael Weinreich","orcid":"0000-0001-7786-1018","position":7,"is_corresponding":false},{"id":380260,"name":"Robert A. Sclafani","orcid":"0000-0002-1100-6489","position":8,"is_corresponding":false},{"id":380261,"name":"Anastasia Baryshnikova","orcid":"0000-0002-0123-2052","position":9,"is_corresponding":false},{"id":52090,"name":"Chad L. Myers","orcid":"0000-0002-1026-5972","position":10,"is_corresponding":false},{"id":94094,"name":"Charles Boone","orcid":"0000-0002-3542-6760","position":11,"is_corresponding":false},{"id":108239,"name":"David Clark","orcid":"0000-0003-0527-8469","position":12,"is_corresponding":false},{"id":380262,"name":"Richard Baker","orcid":"0000-0003-4759-4216","position":13,"is_corresponding":false},{"id":380263,"name":"Munira A. Basrai","orcid":"0000-0003-0628-8052","position":14,"is_corresponding":false},{"id":380255,"name":"Jessica R. Eisenstatt","orcid":"0000-0003-1562-0408","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-18T21:44:45.622639Z","pmid":"32295767","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":[]}