Death-seq identifies regulators of cell death and senolytic therapies.
CRISPR
Death-seq
cell death
death screen
genome-wide
positive selection
pulmonary fibrosis
senescence
senolytics
synthetic lethality
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
03 10 2023
03 10 2023
Historique:
received:
21
05
2023
revised:
07
08
2023
accepted:
17
08
2023
pmc-release:
03
10
2024
medline:
26
10
2023
pubmed:
13
9
2023
entrez:
12
9
2023
Statut:
ppublish
Résumé
Selectively ablating damaged cells is an evolving therapeutic approach for age-related disease. Current methods for genome-wide screens to identify genes whose deletion might promote the death of damaged or senescent cells are generally underpowered because of the short timescales of cell death as well as the difficulty of scaling non-dividing cells. Here, we establish "Death-seq," a positive-selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263. The screen also identified inducers of cell death and senescent cell clearance in models of age-related diseases by a related compound, ABT-199, which alone is not senolytic but exhibits less toxicity than ABT-263. Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identifies drug targets for the treatment of diverse pathological states such as senescence, cancer, and fibrosis.
Identifiants
pubmed: 37699398
pii: S1550-4131(23)00303-0
doi: 10.1016/j.cmet.2023.08.008
pmc: PMC10597643
mid: NIHMS1930877
pii:
doi:
Substances chimiques
navitoclax
XKJ5VVK2WD
Senotherapeutics
0
Aniline Compounds
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1814-1829.e6Subventions
Organisme : BLRD VA
ID : I01 BX002324
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG036695
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR073248
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.C. and T.A.R. have filed a patent application related to the subject matter of this paper. A.C. was formerly a paid consultant during this work for Maze Therapeutics and Rubedo Life Sciences.
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