The Ewing sarcoma protein regulates DNA damage-induced alternative splicing

Mol Cell. 2011 Aug 5;43(3):353-68. doi: 10.1016/j.molcel.2011.05.035.


The Ewing sarcoma (EWS) protein is a member of the TET (TLS/EWS/TAF15) family of RNA- and DNA-binding proteins whose expression is altered in cancer. We report that EWS depletion results in alternative splicing changes of genes involved in DNA repair and genotoxic stress signaling, including ABL1, CHEK2, and MAP4K2. Chromatin and RNA crosslinking immunoprecipitation results indicate that EWS cotranscriptionally binds to its target RNAs. This association is reduced upon irradiation of cells with ultraviolet light, concomitant with transient enrichment of EWS in nucleoli and with alternative splicing changes that parallel those induced by EWS depletion and that lead to reduced c-ABL protein expression. Consistent with the functional relevance of EWS-mediated alternative splicing regulation in DNA damage response, EWS depletion reduces cell viability and proliferation upon UV irradiation, effects that are attenuated by restoring c-ABL expression. These results provide insights into posttranscriptional mechanisms of DNA damage response by a TET protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Cell Nucleolus / metabolism
  • DNA Damage*
  • DNA Repair / genetics
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • RNA Interference
  • RNA Precursors / metabolism
  • RNA, Messenger / metabolism
  • RNA-Binding Protein EWS / analysis
  • RNA-Binding Protein EWS / antagonists & inhibitors
  • RNA-Binding Protein EWS / physiology*


  • RNA Precursors
  • RNA, Messenger
  • RNA-Binding Protein EWS