p53 requires the stress sensor USF1 to direct appropriate cell fate decision.
Genomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway.
CNRS-UMR6290 Genetic and Development Institute of Rennes, GEO Team, Rennes, France; Université de Rennes 1, UEB, SFR Biosit, Rennes, France.
Amine
A
Bouafia
CNRS-UMR6290 Genetic and Development Institute of Rennes, GEO Team, Rennes, France; Université de Rennes 1, UEB, SFR Biosit, Rennes, France.
Sébastien
S
Corre
CNRS-UMR6290 Genetic and Development Institute of Rennes, GEO Team, Rennes, France; Université de Rennes 1, UEB, SFR Biosit, Rennes, France.
David
D
Gilot
CNRS-UMR6290 Genetic and Development Institute of Rennes, GEO Team, Rennes, France; Université de Rennes 1, UEB, SFR Biosit, Rennes, France.
Nicolas
N
Mouchet
University of Cape Town, Department of Human Biology, Faculty of Health Sciences, Cape Town, South Africa.
Sharon
S
Prince
CNRS-UMR6290 Genetic and Development Institute of Rennes, GEO Team, Rennes, France; Université de Rennes 1, UEB, SFR Biosit, Rennes, France; CHU Rennes, Service de génétique moléculaire et génomique, Rennes, France.
Marie-Dominique
MD
Galibert
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics*; D060066:Protein Interaction Maps / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D051736:Proto-Oncogene Proteins c-mdm2