Functional genomic screens with death rate analyses reveal mechanisms of drug action
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
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.
I: Nature Chemical Biology, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Functional genomic screens with death rate analyses reveal mechanisms of drug action
AU - Honeywell, Megan E.
AU - Isidor, Marie S.
AU - Harper, Nicholas W.
AU - Fontana, Rachel E.
AU - Birdsall, Gavin A.
AU - Cruz-Gordillo, Peter
AU - Porto, Sydney A.
AU - Jerome, Madison
AU - Fraser, Cameron S.
AU - Sarosiek, Kristopher A.
AU - Guertin, David A.
AU - Spinelli, Jessica B.
AU - Lee, Michael J.
N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
PY - 2024
Y1 - 2024
N2 - 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. (Figure presented.).
AB - 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. (Figure presented.).
U2 - 10.1038/s41589-024-01584-7
DO - 10.1038/s41589-024-01584-7
M3 - Journal article
C2 - 38480981
AN - SCOPUS:85187658554
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
ER -
ID: 390289687