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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

  • Megan E. Honeywell
  • Isidor, Marie Sophie
  • Nicholas W. Harper
  • Rachel E. Fontana
  • Gavin A. Birdsall
  • Peter Cruz-Gordillo
  • Sydney A. Porto
  • Madison Jerome
  • Cameron S. Fraser
  • Kristopher A. Sarosiek
  • David A. Guertin
  • Jessica B. Spinelli
  • Michael J. Lee
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.
OriginalsprogEngelsk
TidsskriftNature Chemical Biology
ISSN1552-4450
DOI
StatusE-pub ahead of print - 2024

Bibliografisk note

Funding Information:
We thank current and past members of the UMass Chan Medical School DSB community for their helpful comments and critiques during the design and execution of this study. Additionally, we thank T. Leete for assistance with training in an early stage of this project; C. Navarro for thoughtful comments and editing of this paper; C. Baer and the UMass Chan SCOPE Core for assistance with some microscopy experiments; A. Mitchell for providing an H2B-mCherry plasmid; T. Fazzio for providing the pX330 plasmid; T. Fortier, E. Baehrecke and the UMass Chan Electron Microscopy Core for assistance with transmission electron microscopy experiments; and M. Green and D. Kim for providing access to some of the cell lines used in this study. M.S.I. is supported by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center based at the University of Copenhagen, and partially funded by an unconditional donation from the Novo Nordisk Foundation (grant number NNF18CC0034900). This work was supported by grants from the National Institutes of Health/National Institute of General Medical Sciences (R01GM127559 to M.J.L.), the National Cancer Institute (F31CA268847 to M.E.H.), the JKTG Foundation (to M.J.L.) and the American Cancer Society (RSG-17-011-01 to M.J.L.).

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

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