UBE2G1 governs the destruction of cereblon neomorphic substrates

Area of Science:

• Molecular Biology
• Cancer Biology
• Pharmacology

Background:

• Cereblon modulating agents (CMs) like lenalidomide repurpose the CRL4CRBN E3 ubiquitin ligase complex.
• CMs induce degradation of specific neomorphic substrates via polyubiquitination, but the E2 ubiquitin-conjugating enzymes involved were unknown.

Purpose of the Study:

• To identify the E2 ubiquitin-conjugating enzymes responsible for CRL4CRBN substrate polyubiquitination.
• To investigate the role of these enzymes in CM-induced substrate degradation and antitumor activity.

Main Methods:

• Investigated the cooperative function of UBE2G1 and UBE2D3 in K48-linked polyubiquitination of CRL4CRBN substrates.
• Assessed the impact of UBE2G1 blockade on substrate ubiquitination, degradation, and CM-induced antitumor effects.
• Examined drug resistance mechanisms in UBE2G1-deficient myeloma cells.

Main Results:

• UBE2G1 and UBE2D3 cooperatively promote K48-linked polyubiquitination of CRL4CRBN substrates through a sequential mechanism.
• Blocking UBE2G1 significantly reduced substrate ubiquitination and degradation, diminishing the antitumor activity of tested CMs.
• UBE2G1 inactivation conferred resistance to lenalidomide and pomalidomide by preventing IKZF1/IKZF3 degradation, but not to the more potent CC-220.

Conclusions:

• UBE2G1 is a key E2 enzyme in the CRL4CRBN E3 ligase complex for CM-induced neomorphic substrate degradation.
• Loss of UBE2G1 activity can lead to clinical resistance to certain CMs, highlighting its importance in therapeutic efficacy.
• Further research is warranted to explore the link between UBE2G1 activity and clinical resistance to CRL4CRBN-hijacking drugs.