{"doi":"10.1093/narcan/zcad058","title":"An impaired ubiquitin-proteasome system increases APOBEC3A abundance","abstract":"Apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases cause genetic instability during cancer development. Elevated APOBEC3A (A3A) levels result in APOBEC signature mutations; however, mechanisms regulating A3A abundance in breast cancer are unknown. Here, we show that dysregulating the ubiquitin-proteasome system with proteasome inhibitors, including Food and Drug Administration-approved anticancer drugs, increased A3A abundance in breast cancer and multiple myeloma cell lines. Unexpectedly, elevated A3A occurs via an ∼100-fold increase in A3A mRNA levels, indicating that proteasome inhibition triggers a transcriptional response as opposed to or in addition to blocking A3A degradation. This transcriptional regulation is mediated in part through FBXO22, a protein that functions in SKP1-cullin-F-box ubiquitin ligase complexes and becomes dysregulated during carcinogenesis. Proteasome inhibitors increased cellular cytidine deaminase activity, decreased cellular proliferation and increased genomic DNA damage in an A3A-dependent manner. Our findings suggest that proteasome dysfunction, either acquired during cancer development or induced therapeutically, could increase A3A-induced genetic heterogeneity and thereby influence therapeutic responses in patients.","journal":"NAR Cancer","year":2023,"id":376278,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1139113,"name":"Madeline A. Dennis","orcid":"0000-0002-0859-0194","position":1,"is_corresponding":false},{"id":250638,"name":"Alexandra Dananberg","orcid":"0000-0002-2447-0053","position":2,"is_corresponding":false},{"id":1139521,"name":"Chris D. Collins","orcid":null,"position":3,"is_corresponding":false},{"id":340264,"name":"Hannah E. Wilson","orcid":"0009-0008-6520-9215","position":4,"is_corresponding":false},{"id":1139522,"name":"Jordyn Meekma","orcid":null,"position":5,"is_corresponding":false},{"id":369307,"name":"Marina I. Savenkova","orcid":"0000-0001-8325-0141","position":6,"is_corresponding":false},{"id":1139114,"name":"Daniel Ng","orcid":"0000-0002-9635-2646","position":7,"is_corresponding":false},{"id":1139115,"name":"Chelsea A. Osbron","orcid":"0000-0003-1210-9284","position":8,"is_corresponding":false},{"id":610908,"name":"Tony M. Mertz","orcid":"0000-0002-9243-4062","position":9,"is_corresponding":false},{"id":305171,"name":"Alan G. Goodman","orcid":"0000-0001-6394-332X","position":10,"is_corresponding":false},{"id":563282,"name":"Sascha H. Duttke","orcid":"0000-0003-4717-000X","position":11,"is_corresponding":false},{"id":250636,"name":"John Maciejowski","orcid":"0000-0001-8134-9308","position":12,"is_corresponding":false},{"id":13970,"name":"Steven A. Roberts","orcid":"0000-0002-3628-5808","position":13,"is_corresponding":false},{"id":476317,"name":"Margo Coxon","orcid":null,"position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T01:16:28.318749Z","pmid":"38155930","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":[]}