Institute of Experimental Immunology, University of Zurich, Zurich 8057, Switzerland.
Living Systems Institute, University of Exeter, Exeter EX4 4QD, UK.
Nucleic Acids Res. 2024 Jan 25;52(2):e8. doi: 10.1093/nar/gkad1118.
Prokaryotic and eukaryotic adaptive immunity differ considerably. Yet, their fundamental mechanisms of gene editing via Cas9 and activation-induced deaminase (AID), respectively, can be conveniently complimentary. Cas9 is an RNA targeted dual nuclease expressed in several bacterial species. AID is a cytosine deaminase expressed in germinal centre B cells to mediate genomic antibody diversification. AID can also mediate epigenomic reprogramming via active DNA demethylation. It is known that sequence motifs, nucleic acid structures, and associated co-factors affect AID activity. But despite repeated attempts, deciphering AID's intrinsic catalytic activities and harnessing its targeted recruitment to DNA is still intractable. Even recent cytosine base editors are unable to fully recapitulate AID's genomic and epigenomic editing properties. Here, we describe the first instance of a modular AID-based editor that recapitulates the full spectrum of genomic and epigenomic editing activity. Our 'Swiss army knife' toolbox will help better understand AID biology per se as well as improve targeted genomic and epigenomic editing.
原核生物和真核生物的适应性免疫有很大的不同。然而，它们分别通过 Cas9 和激活诱导脱氨酶 (AID) 进行基因编辑的基本机制可以方便地互补。Cas9 是一种在几种细菌中表达的靶向 RNA 的双核酸酶。AID 是生发中心 B 细胞中表达的胞嘧啶脱氨酶，介导基因组抗体多样化。AID 还可以通过主动 DNA 去甲基化来介导表观基因组重编程。已知序列基序、核酸结构和相关辅助因子会影响 AID 的活性。但是，尽管反复尝试，AID 的内在催化活性的破译和其靶向招募到 DNA 仍然难以解决。即使是最近的胞嘧啶碱基编辑器也无法完全重现 AID 的基因组和表观基因组编辑特性。在这里，我们描述了第一个基于模块化 AID 的编辑器的实例，该编辑器重现了基因组和表观基因组编辑的全谱。我们的“瑞士军刀”工具箱将有助于更好地了解 AID 生物学本身，并改善靶向基因组和表观基因组编辑。
