An impaired ubiquitin-proteasome system increases APOBEC3A abundance Journal Article


Authors: Coxon, M.; Dennis, M. A.; Dananberg, A.; Collins, C. D.; Wilson, H. E.; Meekma, J.; Savenkova, M.; Ng, D.; Osbron, C. A.; Mertz, T. M.; Goodman, A. G.; Duttke, S. H.; Maciejowski, J.; Roberts, S. A.
Article 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 similar to 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. Graphical Abstract created with BioRender.com
Keywords: proteins; inhibitor; transcription; human cancers; mutagenesis; expression; dna-damage; mechanisms; strand; mutational signatures
Journal Title: NAR Cancer
Volume: 5
Issue: 4
ISSN: 2632-8674
Publisher: Oxford University Press  
Date Published: 2023-12-01
Start Page: zcad058
Language: English
ACCESSION: WOS:001127600400001
DOI: 10.1093/narcan/zcad058
PROVIDER: wos
PMCID: PMC10753533
PUBMED: 38155930
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Wos
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