An impaired ubiquitin-proteasome system increases APOBEC3A abundance.

Autor:	Coxon M; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Dennis MA; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Dananberg A; Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Collins CD; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Wilson HE; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Meekma J; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Savenkova MI; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Ng D; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Osbron CA; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Mertz TM; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA.; Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont, Burlington, VT 05405, USA., Goodman AG; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Duttke SH; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA., Maciejowski J; Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Roberts SA; School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA.; Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont, Burlington, VT 05405, USA.
Jazyk:	angličtina
Zdroj:	NAR cancer [NAR Cancer] 2023 Dec 19; Vol. 5 (4), pp. zcad058. Date of Electronic Publication: 2023 Dec 19 (Print Publication: 2023).
DOI:	10.1093/narcan/zcad058
Abstrakt:	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. (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu