dTAG

dTAG is a targeted protein degradation platform that enables rapid, selective elimination of proteins of interest by combining degron tagging with small-molecule degraders. It is used to study protein function and dynamics by providing precise temporal control over protein abundance in cells and organisms.

The core concept involves fusing a protein of interest to a mutant version of FKBP12, commonly designated FKBP12F36V, which serves as a degradation tag. Small, heterobifunctional molecules, such as dTAG compounds, simultaneously bind the FKBP12F36V tag and an E3 ubiquitin ligase component (most commonly cereblon, CRBN). This recruitment brings the target protein into the ubiquitin–proteasome pathway, tagging it for rapid degradation. After administration, degradation typically occurs within hours and is reversible: removing the degrader allows new protein synthesis to restore target levels.

dTAG has been applied across diverse cell types, primary cells, and animal models to investigate protein function, signaling pathways, and gene networks with tight temporal resolution. The approach is compatible with standard genetic tagging methods and can be integrated with other functional genomics tools.

Advantages of dTAG include fast and tunable degradation, high specificity for the tagged target, and reversibility, enabling dynamic studies of protein roles. It complements other degron systems and endows researchers with a controllable on/off switch for protein abundance without permanent genetic loss.

Limitations include the need to genetically tag the protein of interest, which can potentially affect function or localization; possible off-target effects of degraders; and considerations about in vivo delivery and tissue exposure. Despite these, dTAG remains a widely used tool for dissecting protein function in cellular and organismal contexts.