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Mapping the Human Kinome in Response to DNA Damage.

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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Owusu M,Bannauer P,Ferreira da Silva J,Mourikis TP,Jones A,Májek P,Caldera M,Wiedner M,Lardeau CH,Mueller AC,Menche J,Kubicek S,Ciccarelli FD,Loizou JI

doi

10.1016/j.celrep.2018.12.087

subject

Has Abstract

pub_date

2019-01-15 00:00:00

pages

555-563.e6

issue

3

issn

2211-1247

pii

S2211-1247(18)32047-3

journal_volume

26

pub_type

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