A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest.


Cellular responses to stimuli can evolve over time, resulting in distinct early and late phases in response to a single signal. DNA damage induces a complex response that is largely orchestrated by the transcription factor p53, whose dynamics influence whether a damaged cell will arrest and repair the damage or will initiate cell death. How p53 responses and cellular outcomes evolve in the presence of continuous DNA damage remains unknown. Here, we have found that a subset of cells switches from oscillating to sustained p53 dynamics several days after undergoing damage. The switch results from cell cycle progression in the presence of damaged DNA, which activates the caspase-2-PIDDosome, a complex that stabilizes p53 by inactivating its negative regulator MDM2. This work defines a molecular pathway that is activated if the canonical checkpoints fail to halt mitosis in the presence of damaged DNA.





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Publication Info

Tsabar, Michael, Caroline S Mock, Veena Venkatachalam, Jose Reyes, Kyle W Karhohs, Trudy G Oliver, Aviv Regev, Ashwini Jambhekar, et al. (2020). A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest. Cell reports, 32(5). p. 107995. 10.1016/j.celrep.2020.107995 Retrieved from https://hdl.handle.net/10161/25566.

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Trudy G Oliver

Professor of Pharmacology and Cancer Biology

The Oliver Lab is focused on understanding the biology of under-studied subtypes of lung cancer, specifically squamous and small cell lung cancer (SCLC). We investigate mechanisms of tumor initiation, progression, plasticity, and drug resistance to uncover vulnerabilities that can be therapeutically targeted. We capitalize on state-of-the-art mouse and patient-derived models to identify and test novel treatment strategies, with the goal of translating these findings to the clinic. 

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