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  1. Article ; Online: Functional genomic screens with death rate analyses reveal mechanisms of drug action.

    Honeywell, Megan E / Isidor, Marie S / Harper, Nicholas W / Fontana, Rachel E / Birdsall, Gavin A / Cruz-Gordillo, Peter / Porto, Sydney A / Jerome, Madison / Fraser, Cameron S / Sarosiek, Kristopher A / Guertin, David A / Spinelli, Jessica B / Lee, Michael J

    Nature chemical biology

    2024  

    Abstract: A common approach for understanding how drugs induce their therapeutic effects is to identify the genetic determinants of drug sensitivity. Because 'chemo-genetic profiles' are performed in a pooled format, inference of gene function is subject to ... ...

    Abstract A common approach for understanding how drugs induce their therapeutic effects is to identify the genetic determinants of drug sensitivity. Because 'chemo-genetic profiles' are performed in a pooled format, inference of gene function is subject to several confounding influences related to variation in growth rates between clones. In this study, we developed Method for Evaluating Death Using a Simulation-assisted Approach (MEDUSA), which uses time-resolved measurements, along with model-driven constraints, to reveal the combination of growth and death rates that generated the observed drug response. MEDUSA is uniquely effective at identifying death regulatory genes. We apply MEDUSA to characterize DNA damage-induced lethality in the presence and absence of p53. Loss of p53 switches the mechanism of DNA damage-induced death from apoptosis to a non-apoptotic death that requires high respiration. These findings demonstrate the utility of MEDUSA both for determining the genetic dependencies of lethality and for revealing opportunities to potentiate chemo-efficacy in a cancer-specific manner.
    Language English
    Publishing date 2024-03-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-024-01584-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: p53 controls choice between apoptotic and non-apoptotic death following DNA damage.

    Honeywell, Megan E / Isidor, Marie S / Harper, Nicholas W / Fontana, Rachel E / Cruz-Gordillo, Peter / Porto, Sydney A / Fraser, Cameron S / Sarosiek, Kristopher A / Guertin, David A / Spinelli, Jessica B / Lee, Michael J

    bioRxiv : the preprint server for biology

    2023  

    Abstract: DNA damage can activate apoptotic and non-apoptotic forms of cell death; however, it remains unclear what features dictate which type of cell death is activated. We report that p53 controls the choice between apoptotic and non-apoptotic death following ... ...

    Abstract DNA damage can activate apoptotic and non-apoptotic forms of cell death; however, it remains unclear what features dictate which type of cell death is activated. We report that p53 controls the choice between apoptotic and non-apoptotic death following exposure to DNA damage. In contrast to the conventional model, which suggests that p53-deficient cells should be resistant to DNA damage-induced cell death, we find that p53-deficient cells die at high rates following DNA damage, but exclusively using non-apoptotic mechanisms. Our experimental data and computational modeling reveal that non-apoptotic death in p53-deficient cells has not been observed due to use of assays that are either insensitive to cell death, or that specifically score apoptotic cells. Using functional genetic screening - with an analysis that enables computational inference of the drug-induced death rate - we find in p53-deficient cells that DNA damage activates a mitochondrial respiration-dependent form of cell death, called MPT-driven necrosis. Cells deficient for p53 have high basal respiration, which primes MPT-driven necrosis. Finally, using metabolite profiling, we identified mitochondrial activity-dependent metabolic vulnerabilities that can be targeted to potentiate the lethality of DNA damage specifically in p53-deficient cells. Our findings reveal how the dual functions of p53 in regulating mitochondrial activity and the DNA damage response combine to facilitate the choice between apoptotic and non-apoptotic death.
    Language English
    Publishing date 2023-05-16
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.01.17.524444
    Database MEDical Literature Analysis and Retrieval System OnLINE

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