DNA-damage inducible 1 homolog 2 (DDI2)

DNA-damage inducible 1 homolog 2 (DDI2) is a ubiquitin-directed aspartyl endoprotease implicated in the maintenance of proteostasis and genome stability in mammalian cells. It functions as a proteasomal shuttling factor and specifically mediates the proteolytic cleavage and activation of the transcription factor NRF1 (NFE2L1) in response to proteasome dysfunction, enabling compensatory upregulation of proteasome subunit genes. DDI2 requires its substrates to be heavily polyubiquitylated for cleavage, acting as a sensor of abnormal protein accumulation. Loss or inhibition of DDI2 increases sensitivity to proteasome inhibitors such as bortezomib, a feature with potential relevance for cancer therapy, particularly in overcoming drug resistance in multiple myeloma. DDI2 also plays a role in DNA replication stress response by removing replication fork protein RTF2, supporting genome integrity. Structurally, DDI2 contains a ubiquitin-like (UBL) domain, a retroviral protease-like (RVP) domain, and a ubiquitin-interacting motif (UIM), but lacks binding to di-ubiquitin chains as a full-length protein.

Other names

Protein DDI1 homolog 2DDI2DNA damage inducible 1 homolog 2DNA-damage inducible protein 2MGC14844

Proteasome inhibitors (e.g., bortezomib) result in compensatory activation of NRF1 via DDI2-dependent proteolysis; blockade or loss of DDI2 sensitizes cells to proteasome inhibitors by impairing this bounce-back response