APOBEC3A is the predominant global editor of cytosines in human mRNAs and in single-strand RNA viruses

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• APOBEC cytidine deaminases modify DNA and RNA by converting cytosines to uracils.
• APOBEC3A is known to cause DNA hypermutation in cancer.
• The specific RNA editing motifs and roles of APOBECs in RNA editing are not well understood.

Purpose of the Study:

• To identify mRNA edits and diagnostic editing motifs for individual APOBEC enzymes in RNA.
• To determine the predominant APOBEC enzyme responsible for global RNA editing.
• To investigate the role of APOBEC3A-mediated RNA editing in human cells and viral evolution.

Main Methods:

• Parallel DNA and RNA sequencing in yeast and human cells overexpressing APOBEC enzymes.
• Motif-centered statistical analyses to identify preferred RNA editing motifs.
• Analysis of editing motifs in human cancers, blood cells, and viral RNA genomes.

Main Results:

• APOBEC3A overexpression showed a strong preference for the uCg trinucleotide motif in RNA.
• The editing motif preference was enhanced when cytosines were in a 3' base of a loop within a hairpin-loop structure.
• APOBEC3A-like motifs were enriched in human cancers, blood cells, and RNA viruses like SARS-CoV-2, rubella, and poliovirus.

Conclusions:

• APOBEC3A is identified as the predominant global APOBEC RNA editor.
• APOBEC3A-mediated RNA editing has significant potential to influence cell physiology.
• APOBEC3A plays a crucial role in viral RNA genome evolution and has implications for viral pathogenesis.