Functional genomic screens with death rate analyses reveal mechanisms of drug action

Research output: Contribution to journal › Journal article › Research › peer-review

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.

In: Nature Chemical Biology, 2024.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Honeywell, ME, Isidor, MS, Harper, NW, Fontana, RE, Birdsall, GA, Cruz-Gordillo, P, Porto, SA, Jerome, M, Fraser, CS, Sarosiek, KA, Guertin, DA, Spinelli, JB & Lee, MJ 2024, 'Functional genomic screens with death rate analyses reveal mechanisms of drug action', Nature Chemical Biology. https://doi.org/10.1038/s41589-024-01584-7

APA

Honeywell, M. E., Isidor, M. S., Harper, N. W., Fontana, R. E., Birdsall, G. A., Cruz-Gordillo, P., Porto, S. A., Jerome, M., Fraser, C. S., Sarosiek, K. A., Guertin, D. A., Spinelli, J. B., & Lee, M. J. (2024). Functional genomic screens with death rate analyses reveal mechanisms of drug action. Nature Chemical Biology. https://doi.org/10.1038/s41589-024-01584-7

Vancouver

Honeywell ME, Isidor MS, Harper NW, Fontana RE, Birdsall GA, Cruz-Gordillo P et al. Functional genomic screens with death rate analyses reveal mechanisms of drug action. Nature Chemical Biology. 2024. https://doi.org/10.1038/s41589-024-01584-7

Author

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. / Functional genomic screens with death rate analyses reveal mechanisms of drug action. In: Nature Chemical Biology. 2024.

Bibtex

@article{71739b89ee68459786c27b3deeecf1f5,
title = "Functional genomic screens with death rate analyses reveal mechanisms of drug action",
abstract = "A common approach for understanding how drugs induce their therapeutic effects is to identify the genetic determinants of drug sensitivity. Because {\textquoteleft}chemo-genetic profiles{\textquoteright} 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.).",
author = "Honeywell, {Megan E.} and Isidor, {Marie S.} and Harper, {Nicholas W.} and Fontana, {Rachel E.} and Birdsall, {Gavin A.} and Peter Cruz-Gordillo and Porto, {Sydney A.} and Madison Jerome and Fraser, {Cameron S.} and Sarosiek, {Kristopher A.} and Guertin, {David A.} and Spinelli, {Jessica B.} and Lee, {Michael J.}",
note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",
year = "2024",
doi = "10.1038/s41589-024-01584-7",
language = "English",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "nature publishing group",

}

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