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An impaired ubiquitin-proteasome system increases APOBEC3A abundance.
- Source :
-
NAR cancer [NAR Cancer] 2023 Dec 19; Vol. 5 (4), pp. zcad058. Date of Electronic Publication: 2023 Dec 19 (Print Publication: 2023). - Publication Year :
- 2023
-
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.<br /> (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.)
Details
- Language :
- English
- ISSN :
- 2632-8674
- Volume :
- 5
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- NAR cancer
- Publication Type :
- Academic Journal
- Accession number :
- 38155930
- Full Text :
- https://doi.org/10.1093/narcan/zcad058