title: Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells.
abstract: 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.
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, California.
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Shim
authors.affiliation: Longevity Institute, Davis School of Gerontology, University of Southern California, Los Angeles, California.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.affiliation: Longevity Institute, Davis School of Gerontology, University of Southern California, Los Angeles, California.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandhorst
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, California. Longevity Institute, Davis School of Gerontology, University of Southern California, Los Angeles, California. IFOM, FIRC Institute of Molecular Oncology, Milano, Italy. vlongo@usc.edu.
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D013217:Starvation / Q000378:metabolism*; D058207:Sumoylation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D000099270:Y-Family DNA Polymerases
chemical_list: D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C485891:PIAS4 protein, human; C495901:TP53 protein, human; C429004:REV1 protein, human; D000099270:Y-Family DNA Polymerases