Abstract
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.
Highlights
Genomic instability is a central hallmark of cancer, where DNA damaging agents play an important role [1,2]
The tumor suppressor p53 has a central role in orchestrating cellular responses to genotoxic stress
We demonstrate that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) is required for immediate p53 stabilization and appropriate cell fate decisions following genotoxic stress
Summary
Genomic instability is a central hallmark of cancer, where DNA damaging agents play an important role [1,2]. In DNA-damaged eukaryotic cells, genome integrity is maintained by an immediate and inducible protective program. This program requires dedicated sensors that drive and regulate the cellular response, by monitoring DNA-repair and if required by forcing damaged-cells into cell death pathways [3]. When these sensors are compromised, sensitivity to mutagenic agents is increased and the mutation rate speeds up, allowing tumor development. The extent of DNA lesions and the capacity of dedicated sensors to direct a proper response are determining parameters of cell fate
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