Addressing the Blind Spots of Deaminase Base Editors with CRISPR-Cas Glycosylase-Based Editors.

Abstract

The emergence of CRISPR base editors signifies a pivotal shift in genome editing, moving beyond the "cut-and-paste" approach into an era of precise "chemical rewriting." While early editors including CBEs and ABEs enabled efficient base transitions by combining deaminases with Cas9 nickase, their core mechanism limited their application to transition mutations, leaving nearly half of disease-causing transversions unresolved. This review outlines the transformation of DNA glycosylases from unwanted side-effect generators into core drivers of base editor evolution. Through strategic protein engineering, glycosylases have been harnessed to create novel editors that mediate crucial transversion edits, substantially expanding the targeting landscape of precision genome editing. We will examine how these engineered glycosylases achieve programmable DNA rewriting through redirected DNA repair pathways, compare emerging and conventional editors, and explore applications in genetic therapy and functional genomics while addressing ongoing challenges in specificity and delivery. Finally, we envision next-generation editors equipped with artificial intelligence-designed glycosylases capable of spatiotemporally controlled genome manipulation.