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APOBEC3 Cytidine Deaminases: Discovery of Novel C-to-U RNA Editing Enzymes

Dr Bora E. Baysal

Associate Professor of Oncology

Department of Pathology & Laboratory Medicine

Roswell Park Cancer Institute

 

 

RNA editing can modify and diversify protein functions without mutating the DNA and is essential for normal life and development. We recently described the identification of human APOBEC3A and APOBEC3G cytidine deaminases as novel C-to-U RNA editing enzymes that induces site-specific RNA editing of hundreds of genes. APOBEC3s belong to seven-member family of the APOBEC3 cytidine deaminases which play an important role in viral restriction. APOBEC3A edits the transcriptome in pro-inflammatory macrophages and monocytes in response to interferons or hypoxia.

 

We found that transient overexpression of APOBEC3A and APOBEC3G in HEK293T cell line causes C-to-U RNA editing of hundreds to thousands of genes. Site-directed mutagenesis studies demonstrate that conserved zinc-coordinating catalytic residues are essential for RNA editing activity. RNA mutagenesis studies show that stem-loop structures in substrate RNAs play an important role in selection of the edited sites. Physiologic studies reveal that normoxic inhibition of mitochondrial complex II by atpenin A5 or of complex III by myxothiazol mimics hypoxia by inducing the hypoxic transcriptome and APOBEC3A-mediated RNA editing in monocytes. We find no evidence for involvement of hypoxia-inducible factor-1 in hypoxic transcriptomic responses in monocytes. Thus, mitochondria play a key role in the hypoxic induction of RNA editing by APOBEC3A in monocytes via a distinct retrograde signaling pathway. Collectively, our studies reveal a novel inducible cellular RNA editing system catalyzed by APOBEC3A. Cellular RNA editing may antagonize viral infections by preventing availability of the host factors for viruses. Aberrant expression or activity of APOBEC3A in non-immune cells may predispose to chronic diseases by mutating the mRNAs of disease-predisposing genes. 

 

 

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