An impaired ubiquitin-proteasome system increases APOBEC3A abundance

Author:

Coxon Margo1,Dennis Madeline A1,Dananberg Alexandra2,Collins Christopher D1,Wilson Hannah E1,Meekma Jordyn1,Savenkova Marina I1,Ng Daniel1,Osbron Chelsea A1,Mertz Tony M13,Goodman Alan G1,Duttke Sascha H1ORCID,Maciejowski John2,Roberts Steven A13ORCID

Affiliation:

1. School of Molecular Biosciences, Washington State University , Pullman , WA 99164-7520 , USA

2. Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center , New York , NY 10065 , USA

3. Department of Microbiology and Molecular Genetics, University of Vermont Cancer Center, University of Vermont , Burlington , VT 05405 , USA

Abstract

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.

Funder

National Cancer Institute

National Institute of General Medical Sciences

National Institute of Allergy and Infectious Diseases

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

Reference63 articles.

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