Direct Protein Degradation: Emerging Tools to Probe Biological Complexity in Mammalian Systems

Conditional degron approaches for acute and reversible protein depletion have become standard tools for studying gene function in cells and model organisms. Traditional gene perturbation methods have advanced gene function studies but are limited by slow kinetics, potential irreversibility, and lethality when targeting essential genes. To overcome these limitations, tag-based and antibody-based direct protein degradation technologies have been developed. These direct protein degradation systems utilize endogenous protein degradation pathways to achieve rapid and reversible protein depletion. When combined with genome editing, these systems provide precise temporal-and in some cases, spatial-control over endogenous protein expression. In this review, we will discuss the current status of tag-based and antibody-based direct protein degron technologies. We aim to provide a comprehensive guide for selecting these tools, highlighting their context-dependent applications and potential improvements to enhance efficiency and reliability.