Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells

Cancer Res. 2015 Mar 15;75(6):1056-67. doi: 10.1158/0008-5472.CAN-14-2249. Epub 2015 Jan 22.


Short-term starvation or fasting can augment cancer treatment efficacy and can be effective in delaying cancer progression in the absence of chemotherapy, but the underlying molecular mechanisms of action remain elusive. Here, we describe the role of REV1, a specialized DNA polymerase involved in DNA repair, as an important signaling node linking nutrient sensing and metabolic control to cell fate. We show that REV1 is a novel binding partner of the tumor suppressor p53 and regulates its activity. Under starvation, REV1 is modified by SUMO2/3, resulting in the relief of REV1's inhibition of p53 and enhancing p53's effects on proapoptotic gene expression and apoptosis in breast cancer and melanoma cells. Thus, fasting in part through its effect on REV1 is a promising nontoxic strategy to increase p53-dependent cell death and to enhance the efficacy of cancer therapies.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Female
  • Humans
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / metabolism*
  • Nucleotidyltransferases / metabolism*
  • Poly-ADP-Ribose Binding Proteins
  • Protein Inhibitors of Activated STAT / physiology
  • Protein Processing, Post-Translational
  • Reactive Oxygen Species / metabolism
  • Starvation / metabolism*
  • Sumoylation*
  • Tumor Suppressor Protein p53 / physiology*
  • Ubiquitin-Protein Ligases / physiology


  • Nuclear Proteins
  • PIAS4 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Protein Inhibitors of Activated STAT
  • Reactive Oxygen Species
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases
  • Nucleotidyltransferases
  • REV1 protein, human