Mapping the Human Kinome in Response to DNA Damage.
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Embargo End Date
ICR Authors
Authors
Owusu, M
Bannauer, P
Ferreira da Silva, J
Mourikis, TP
Jones, A
Májek, P
Caldera, M
Wiedner, M
Lardeau, C-H
Mueller, AC
Menche, J
Kubicek, S
Ciccarelli, FD
Loizou, JI
Bannauer, P
Ferreira da Silva, J
Mourikis, TP
Jones, A
Májek, P
Caldera, M
Wiedner, M
Lardeau, C-H
Mueller, AC
Menche, J
Kubicek, S
Ciccarelli, FD
Loizou, JI
Document Type
Journal Article
Date
2019-01-15
Date Accepted
2018-12-18
Abstract
We provide a catalog for the effects of the human kinome on cell survival in response to DNA-damaging agents, covering all major DNA repair pathways. By treating 313 kinase-deficient cell lines with ten diverse DNA-damaging agents, including seven commonly used chemotherapeutics, we identified examples of vulnerability and resistance that are kinase specific. To investigate synthetic lethal interactions, we tested the response to carmustine for 25 cell lines by establishing a phenotypic fluorescence-activated cell sorting (FACS) assay designed to validate gene-drug interactions. We show apoptosis, cell cycle changes, and DNA damage and proliferation after alkylation- or crosslink-induced damage. In addition, we reconstitute the cellular sensitivity of DYRK4, EPHB6, MARK3, and PNCK as a proof of principle for our study. Furthermore, using global phosphoproteomics on cells lacking MARK3, we provide evidence for its role in the DNA damage response. Our data suggest that cancers with inactivating mutations in kinases, including MARK3, are particularly vulnerable to alkylating chemotherapeutic agents.
Citation
Cell reports, 2019, 26 (3), pp. 555 - 563.e6
Source Title
Cell reports
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247
Collections
Research Team
Target Val & Genome Stab