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Targeting natural splicing plasticity of APOBEC3B restricts its expression and mutagenic activity.

ABSTRACT: APOBEC3A (A3A) and APOBEC3B (A3B) enzymes drive APOBEC-mediated mutagenesis. Identification of factors affecting the activity of these enzymes could help modulate mutagenesis and associated clinical outcomes. Here, we show that canonical and alternatively spliced A3A and A3B isoforms produce corresponding mutagenic and non-mutagenic enzymes. Increased expression of the mutagenic A3B isoform predicted shorter progression-free survival in bladder cancer. We demonstrate that the production of mutagenic vs. non-mutagenic A3B protein isoforms was considerably affected by inclusion/skipping of exon 5 in A3B. Furthermore, exon 5 skipping, resulting in lower levels of mutagenic A3B enzyme, could be increased in vitro. Specifically, we showed the effects of treatment with an SF3B1 inhibitor affecting spliceosome interaction with a branch point site in intron 4, or with splice-switching oligonucleotides targeting exon 5 of A3B. Our results underscore the clinical role of A3B and implicate alternative splicing of A3B as a mechanism that could be targeted to restrict APOBEC-mediated mutagenesis.

SUBMITTER: Rouf Banday A

PROVIDER: S-EPMC7985488 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Targeting natural splicing plasticity of APOBEC3B restricts its expression and mutagenic activity.

Rouf Banday A A Onabajo Olusegun O OO Lin Seraph Han-Yin SH Obajemu Adeola A Vargas Joselin M JM Delviks-Frankenberry Krista A KA Lamy Philippe P Bayanjargal Ariunaa A Zettelmeyer Clara C Florez-Vargas Oscar O Pathak Vinay K VK Dyrskjøt Lars L Prokunina-Olsson Ludmila L

Communications biology 20210322 1

APOBEC3A (A3A) and APOBEC3B (A3B) enzymes drive APOBEC-mediated mutagenesis. Identification of factors affecting the activity of these enzymes could help modulate mutagenesis and associated clinical outcomes. Here, we show that canonical and alternatively spliced A3A and A3B isoforms produce corresponding mutagenic and non-mutagenic enzymes. Increased expression of the mutagenic A3B isoform predicted shorter progression-free survival in bladder cancer. We demonstrate that the production of mutag ...[more]

PMID: 33753867

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Project description:ObjectiveCervical cancer is one of the leading fatal diseases in women, and the role of Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) in cervical cancer is uncertain.MethodsFour Gene Expression Omnibus (GEO) mRNA microarray datasets were analyzed to identify differentially expressed genes (DEGs) between cervical cancer and normal cervical tissues. The results were validated using a The Cancer Genome Atlas (TCGA)-cervical cancer (CESC) dataset. Expression profiles and patients' clinical data were used to investigate the relationship between APOBEC3B expression and cervical cancer survival. APOBEC3B co-expressed genes were subjected to enrichment analyses, and correlations between APOBEC3B expression and immunologic infiltrates were investigated using Tumor Immune Estimation Resource (TIMER). We generated receiver operating characteristic curve (ROC) curves to evaluate the performance of APOBEC3B expression in predicting cervical cancer prognosis.ResultsFourteen overlapping DEGs were obtained, and APOBEC3B was chosen as a candidate gene. TCGA data further confirmed that APOBEC3B was significantly increased in cervical cancer, relative to normal adjacent tissues, and this expression was associated with poor clinical outcome. Results from quantitative real time polymerase chain reaction (RT-qPCR) and immunohistochemical staining of cervical carcinoma tissues supported these findings. Enrichment analysis showed that APOBEC3B co-expressed genes were mainly enriched in cell cycle, DNA replication and chromosomal region. Moreover, APOBEC3B expression was significantly associated with T stage, M stage, primary therapy outcome and poor clinical prognosis in cervical cancer. Similarly, APOBEC3B was closely correlated with gene markers of diverse immune cells. APOBEC3B expression was an independent indicator of cervical cancer prognosis, according to univariate Cox and ROC analyses.ConclusionHigh APOBEC3B expression is strongly related to a poor prognosis in cervical cancer patients.

Dataset Information

Targeting natural splicing plasticity of APOBEC3B restricts its expression and mutagenic activity.

Publications

Targeting natural splicing plasticity of APOBEC3B restricts its expression and mutagenic activity.

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