Zinc-Binding Domain-Dependent, Deaminase-Independent Actions of Apolipoprotein B mRNA Editing Enzyme, Catalytic Polypeptide 2 (Apobec2) Mediate Its Effect on Zebrafish Retina Regeneration

The Apobec/AID family of cytosine deaminases can deaminate cytosine and thereby contribute to adaptive and innate immunity, DNA demethylation and the modification of cellular mRNAs. Unique among this family is Apobec2 whose enzymatic activity has been questioned and whose function remains poorly explored. We recently reported that zebrafish Apobec2a and Apobec2b (Apobec2a,2b) regulate retina regeneration; however, their mechanism of action remained unknown. Here we show that although Apobec2a,2b lack cytosine deaminase activity, they require a conserved zinc-binding domain to stimulate retina regeneration. Interestingly, we found that human APOBEC2 is able to functionally substitute for Apobec2a,2b during retina regeneration. By identifying Apobec2-interacting proteins, including ubiquitin conjugating enzyme 9 (Ubc9), topoisomerase I binding, arginine/serine rich, E3 ubiquitin protein ligase (Toporsa) and POU class 6 homeobox 2 (Pou6f2), we uncovered that sumoylation regulates Apobec2 subcellular localization and that nuclear Apobec2 controls Pou6f2 binding to DNA. Importantly, mutations in Apobec2's zinc-binding domain diminish its ability to stimulate Pou6f2 binding to DNA and knockdown of Ubc9 or Pou6f2 suppressed retina regeneration.