Mapping the Human Kinome in Response to DNA Damage

Michel Owusu, Peter Bannauer, Joana Ferreira da Silva, Thanos P Mourikis, Alistair Jones, Peter Májek, Michael Caldera, Marc Wiedner, Charles-Hugues Lardeau, André C Mueller, Jörg Menche, Stefan Kubicek, Francesca D Ciccarelli, Joanna I Loizou

    Research output: Contribution to journalArticlepeer-review

    15 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)555-563.e6
    JournalCell Reports
    Volume26
    Issue number3
    Early online date15 Jan 2019
    DOIs
    Publication statusE-pub ahead of print - 15 Jan 2019

    Keywords

    • DNA damage
    • carmustine
    • chemotherapeutics
    • kinase
    • kinome
    • synthetic lethality
    • temozolomide

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