Ligand-induced degrons for studying nuclear functions

Abstract

Conditional control of protein expression facilitates studies of nuclear functions, which are highly dynamic and tightly linked to the cell cycle in proliferating cells. However, conditional methodologies that target a pre-translational process, such as siRNA and conditional knockout, require a relatively long time for target protein depletion; thus, there is a danger of accumulation of secondary effects that would obscure the primary defect before observation. Therefore, ligand-induced degron technologies draw attention to archive acute depletion of a degron-fused protein via the ubiquitin-proteasome pathway in the presence of an inducing ligand that promotes the association between a degron-fused protein and an E3 ubiquitin ligase. These chemical-genetic technologies are based on an immunomodulatory drug, proteolysis-targeting chimera or a phytohormone. Here, I review the current ligand-induced degrons and present successful cases in which new nuclear functions were identified using dTAG or an auxin-inducible degron. I also review latest ligand-induced degrons based on the BRD4 bromo-domain. Finally, I discuss the similarities and differences between dTAG and AID methodologies.