Mapping the Human Kinome in Response to DNA Damage. Academic Article uri icon

Overview

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.

publication date

  • January 15, 2019

Research

keywords

  • DNA Damage

Identity

Scopus Document Identifier

  • 85059682456

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2018.12.087

PubMed ID

  • 30650350

Additional Document Info

volume

  • 26

issue

  • 3