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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 \u223c100-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\u2013cullin\u2013F-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.<\/jats:p>","DOI":"10.1093\/narcan\/zcad058","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T18:38:34Z","timestamp":1703011114000},"source":"Crossref","is-referenced-by-count":5,"title":["An impaired ubiquitin-proteasome system increases APOBEC3A abundance"],"prefix":"10.1093","volume":"5","author":[{"given":"Margo","family":"Coxon","sequence":"first","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline A","family":"Dennis","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Dananberg","sequence":"additional","affiliation":[{"name":"Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center , New York , NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher\u00a0D","family":"Collins","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah\u00a0E","family":"Wilson","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordyn","family":"Meekma","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina\u00a0I","family":"Savenkova","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Ng","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea\u00a0A","family":"Osbron","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony\u00a0M","family":"Mertz","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"},{"name":"Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont , Burlington , VT 05405 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan\u00a0G","family":"Goodman","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4717-000X","authenticated-orcid":false,"given":"Sascha\u00a0H","family":"Duttke","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Maciejowski","sequence":"additional","affiliation":[{"name":"Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center , New York , NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3628-5808","authenticated-orcid":false,"given":"Steven\u00a0A","family":"Roberts","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA"},{"name":"Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont , Burlington , VT 05405 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,19]]},"reference":[{"key":"2024032320175142500_B1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature12477","article-title":"Signatures of mutational processes in human cancer","volume":"500","author":"Alexandrov","year":"2013","journal-title":"Nature"},{"key":"2024032320175142500_B2","first-page":"1","article-title":"The APOBEC3 family of retroelement restriction factors","volume":"371","author":"Refsland","year":"2013","journal-title":"Curr. 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