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

Area of Science:

• Biochemistry and Molecular Biology
• Genetics and Genomics
• Virology

Background:

• APOBEC cytidine deaminases modify DNA and RNA by converting cytosines to uracils.
• APOBEC3A is known to cause DNA hypermutation in cancer, but its role in RNA editing is less understood.
• Specific RNA editing motifs for APOBEC enzymes have not been clearly defined.

Purpose of the Study:

• To identify messenger RNA (mRNA) edits and diagnostic editing motifs associated with individual APOBEC enzymes.
• To determine the predominant APOBEC enzyme responsible for global RNA editing.
• To investigate the potential impact of APOBEC3A RNA editing on cell physiology and viral evolution.

Main Methods:

• Employed parallel DNA and RNA sequencing in yeast and human cells overexpressing individual APOBEC enzymes.
• Utilized motif-centered statistical analyses to identify editing patterns.
• Compared identified motifs with editing data from human cancers, blood cells, and viral RNA genomes.

Main Results:

• Overexpression of APOBEC3A, but not other APOBECs, led to a global enrichment of the uCg trinucleotide motif in RNA.
• APOBEC3A showed a preference for cytosines within hairpin-loop secondary structures.
• The APOBEC3A-like editing motif was enriched in human cancers, blood cells, and the RNA genomes of SARS-CoV-2, rubella virus, and poliovirus.

Conclusions:

• APOBEC3A is identified as the predominant global APOBEC enzyme involved in RNA editing.
• The specific uCg motif within hairpin structures serves as a diagnostic marker for APOBEC3A RNA editing.
• APOBEC3A-mediated RNA editing has significant implications for cellular processes and the evolutionary trajectory of viruses.