Rxivist logo

Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 70,482 bioRxiv papers from 307,800 authors.

UBE2G1 Governs the Destruction of Cereblon Neomorphic Substrates

By Gang Lu, Stephanie Weng, Mary Matyskiela, Xinde Zheng, Wei Fang, Scott Wood, Christine Surka, Reina Mizukoshi, Chin-Chun Lu, Derek Mendy, In Sock Jang, Kai Wang, Mathieu Marella, Suzana Couto, Brian Cathers, James Carmichael, Philip Chamberlain, Mark Rolfe

Posted 09 Aug 2018
bioRxiv DOI: 10.1101/389098 (published DOI: 10.7554/elife.40958)

The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide as well as the novel cereblon modulating agents (CMs) including CC-122, CC-220 and cereblon-based proteolysis-targeting chimaeras (PROTACs) repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with an E1 ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the polyubiquitination of CRL4CRBN neomorphic substrates in a cereblon- and CM-dependent manner via a sequential ubiquitination mechanism: UBE2D3 transforms the neomorphic substrates into mono-ubiquitinated forms, upon which UBE2G1 catalyzes K48-linked polyubiquitin chain extension. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, these findings suggest that loss of UBE2G1 activity might be a resistance mechanism to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins, and that this resistance mechanism can be overcome by next-generation CMs that destroy the same targeted protein more effectively.

Download data

  • Downloaded 549 times
  • Download rankings, all-time:
    • Site-wide: 20,073 out of 70,482
    • In molecular biology: 590 out of 2,265
  • Year to date:
    • Site-wide: 32,882 out of 70,482
  • Since beginning of last month:
    • Site-wide: 30,519 out of 70,482

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide


Sign up for the Rxivist weekly newsletter! (Click here for more details.)