APOBECs orchestrate genomic and epigenomic editing across health and disease

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. HighlightsGenomic 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.

Expression of Human Endogenous Retroviruses in the Human Thymus Along T Cell Development

“…It is worth noting that the HERV expression follows the same kinetics of the expression of APOBECs, HRFs that play a determinant role in the control of retroviral infections (27). Given the role of APOBECs in cell biology (28), their possible impact in T cell selection deserves exploration.…”

Evaluation of Circulating and Archived HIV-1 Integrase Drug-Resistance Variants among Patients on Third-Line ART in Cameroon: Implications for Dolutegravir-Containing Regimens in Resource-Limited Settings

“…Despite all these facts, G140R and G163R are hard to relate to resistance in the present case given that they may have resulted as a consequence of the apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3 (APOBEC3) mutagenesis activity in the proviral DNA ( 58 , 59 ). In effect, APOBEC3 has been studied intensely in the field of virology because it was recognized early on to deaminate cytosines in cDNA reverse transcription intermediates of retroviruses, including HIV-1 ( 58 – 60 ), thus leading to mutations not always related to drug-pressure. Furthermore, even though the impact of these ambiguous mutations on DTG-based ART is not concerning, the potential presence of other major DRMs in minority viral populations (<20% sequencing threshold) needs to be ascertained ( 61 , 62 ).…”

Pan-cancer investigation of C-to-U editing reveals its important role in cancer development and new targets for cancer treatment

“…However, the research on C-to-U editing has been largely lagging behind, especially in cancer ( 3 ), although scattered reports have studied the function of APOBEC enzymes, which are responsible for most C-to-U editing, and their cofactors ( 10 – 12 ). The first and most famous C-to-U editing was in apolipoprotein B mRNA in the small intestine, which gave APOBEC its name ( 13 ).…”