DDI1 (DNA damage-inducible 1) is a multidomain protease that functions as a proteasomal shuttle factor linking the proteasome to DNA replication processes. The protein contains conserved ubiquitin-like (UBL), retroviral protease (RVP), and ubiquitin-associated (UBA) domains that confer distinct activities 1. DDI1 acts as an aspartic-type endopeptidase involved in proteasomal degradation of specific proteins and plays a critical role in DNA replication stress response 2. The protein is essential for cellular survival following replication stress, working with DDI2 to remove RTF2 from stalled replication forks, thereby allowing cell cycle progression and maintaining genome integrity 2. DDI1 also participates in DNA-protein crosslink (DPC) repair, protecting cells against oxidative stress-induced DNA damage 3. Recent evidence suggests DDI1 functions in K48-ubiquitin-dependent proteolysis, where it generates fragments from both soluble and membrane proteins as part of a novel degradative pathway called CUT-UP 4. The protein is regulated by UBE3A-mediated ubiquitination 5 and shows potential therapeutic relevance, as DDI1 depletion enhances susceptibility to certain drugs and compromises parasite development in malaria 1.