WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation

Cell Res. 2017 Feb;27(2):274-293. doi: 10.1038/cr.2016.148. Epub 2016 Dec 13.


Oncogene-induced senescence (OIS) or apoptosis through the DNA-damage response is an important barrier of tumorigenesis. Overcoming this barrier leads to abnormal cell proliferation, genomic instability, and cellular transformation, and finally allows cancers to develop. However, it remains unclear how the OIS barrier is overcome. Here, we show that the E3 ubiquitin ligase WD repeat and SOCS box-containing protein 1 (WSB1) plays a role in overcoming OIS. WSB1 expression in primary cells helps the bypass of OIS, leading to abnormal proliferation and cellular transformation. Mechanistically, WSB1 promotes ATM ubiquitination, resulting in ATM degradation and the escape from OIS. Furthermore, we identify CDKs as the upstream kinase of WSB1. CDK-mediated phosphorylation activates WSB1 by promoting its monomerization. In human cancer tissue and in vitro models, WSB1-induced ATM degradation is an early event during tumorigenic progression. We suggest that WSB1 is one of the key players of early oncogenic events through ATM degradation and destruction of the tumorigenesis barrier. Our work establishes an important mechanism of cancer development and progression in premalignant lesions.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cellular Senescence*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Models, Biological
  • Oncogenes*
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Proteins / chemistry
  • Proteins / metabolism*
  • Proteolysis*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • WSB1 protein, human
  • Wsb1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Ataxia Telangiectasia Mutated Proteins