APOBECs orchestrate genomic and epigenomic editing across health and disease. Issue 11 (November 2021) - Cervantes-Gracia, Karla
Abstract : APOBEC proteins can deaminate cytosine residues in DNA and RNA. This can lead to somatic mutations, DNA breaks, RNA modifications, or DNA demethylation in a selective manner. APOBECs function in various cellular compartments and recognize different nucleic acid motifs and structures. They orchestrate a wide array of genomic and epigenomic modifications, thereby affecting various cellular functions positively or negatively, including immune editing, viral and retroelement restriction, DNA damage responses, DNA demethylation, gene expression, and tissue homeostasis. Furthermore, the cumulative increase in genomic and epigenomic editing with aging could also, at least in part, be attributed to APOBEC function. We synthesize our cumulative understanding of APOBEC activity in a unifying overview and discuss their genomic and epigenomic impact in physiological, pathological, and technological contexts. Highlights: Genomic and epigenomic effects of apolipoprotein B mRNA editing cytosine deaminases (APOBECs) are tightly controlled and are essential for physiological immune and non-immune processes. Pathological APOBEC off-target effects are often observed because of altered catalytic activity or dysregulation, and/or synergies with other predisposing factors such as infections, inflammation, or DNA repair defects. APOBEC mutation signatures are documented in various cancers. They are also involved in autoimmune diseases, triple nucleotide repeat diseases, and diabetes, among others. Possible APOBEC signatures in aging tissues also highlight their potential contribution to this process at the genomic and epigenomic levels. Advances in gene-editing technologies combined with APOBEC mechanistic insights are ushering in the era of APOBECs as therapeutic targets, potentially closing the loop of negative versus positive gene-editing effects.