E2F1 sumoylation as a protective cellular mechanism in oxidative stress response

Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):14958-14969. doi: 10.1073/pnas.1921554117. Epub 2020 Jun 15.


Oxidative stress is a ubiquitous threat to all aerobic organisms and has been implicated in numerous pathological conditions such as cancer. Here we demonstrate a pivotal role for E2F1, a cell cycle regulatory transcription factor, in cell tolerance of oxidative stress. Cells lacking E2F1 are hypersensitive to oxidative stress due to the defects in cell cycle arrest. Oxidative stress inhibits E2F1 transcriptional activity, independent of changes in association with Rb and without decreasing its DNA-binding activity. Upon oxidative insult, SUMO2 is extensively conjugated to E2F1 mainly at lysine 266 residue, which specifically modulates E2F1 transcriptional activity to enhance cell cycle arrest for cell survival. We identify SENP3, a desumoylating enzyme, as an E2F1-interacting partner. Oxidative stress inhibits the interaction between E2F1 and SENP3, which leads to accumulation of sumoylated E2F1. SENP3-deficient cells exhibit hypersumoylation of E2F1 and are resistant to oxidative insult. High levels of SENP3 in breast cancer are associated with elevated levels of E2F targets, high tumor grade, and poor survival. Given the prevalence of elevated levels of SENP3 across numerous cancer types, the SENP3-E2F1 axis may serve as an avenue for therapeutic intervention in cancer.

Keywords: E2F1; SENP3; SUMO2; oxidative stress; sumoylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • E2F1 Transcription Factor / chemistry
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism*
  • Female
  • Humans
  • Oxidative Stress*
  • Protein Binding
  • Small Ubiquitin-Related Modifier Proteins / genetics
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Sumoylation


  • E2F1 Transcription Factor
  • SUMO2 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Cysteine Endopeptidases
  • SENP3 protein, human