The E3 ligase UBR2 regulates cell death under caspase deficiency via Erk/MAPK pathway

Cell Death Dis. 2020 Dec 8;11(12):1041. doi: 10.1038/s41419-020-03258-3.


Escape from cell death is a key event in cancer establishment/progression. While apoptosis is often considered as the main cell death pathway, upon caspase inhibition, cell death is rather delayed than blocked leading to caspase-independent cell death (CICD). Although described for years, CICD's underlying mechanism remains to be identified. Here, we performed a genome-wide siRNA lethality screening and identified the RING-Type E3 Ubiquitin Transferase (UBR2) as a specific regulator of CICD. Strikingly, UBR2 downregulation sensitized cells towards CICD while its overexpression was protective. We established that UBR2-dependent protection from CICD was mediated by the MAPK/Erk pathway. We then observed that UBR2 is overexpressed in several cancers, especially in breast cancers and contributes to CICD resistance. Therefore, our work defines UBR2 as a novel regulator of CICD, found overexpressed in cancer cells, suggesting that its targeting may represent an innovative way to kill tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Autophagy
  • Caspases / deficiency*
  • Caspases / metabolism
  • Cell Death
  • Cell Line, Tumor
  • Cytoprotection
  • Ferroptosis
  • Gene Knockdown Techniques
  • Genome, Human
  • Humans
  • MAP Kinase Signaling System*
  • Models, Biological
  • Necroptosis
  • Ubiquitin-Protein Ligases / metabolism*


  • UBR2 protein, human
  • Ubiquitin-Protein Ligases
  • Caspases