PLoS ONE (Jan 2015)

Functional genomics screening utilizing mutant mouse embryonic stem cells identifies novel radiation-response genes.

  • Kimberly Loesch,
  • Stacy Galaviz,
  • Zaher Hamoui,
  • Ryan Clanton,
  • Gamal Akabani,
  • Michael Deveau,
  • Michael DeJesus,
  • Thomas Ioerger,
  • James C Sacchettini,
  • Deeann Wallis

DOI
https://doi.org/10.1371/journal.pone.0120534
Journal volume & issue
Vol. 10, no. 4
p. e0120534

Abstract

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Elucidating the genetic determinants of radiation response is crucial to optimizing and individualizing radiotherapy for cancer patients. In order to identify genes that are involved in enhanced sensitivity or resistance to radiation, a library of stable mutant murine embryonic stem cells (ESCs), each with a defined mutation, was screened for cell viability and gene expression in response to radiation exposure. We focused on a cancer-relevant subset of over 500 mutant ESC lines. We identified 13 genes; 7 genes that have been previously implicated in radiation response and 6 other genes that have never been implicated in radiation response. After screening, proteomic analysis showed enrichment for genes involved in cellular component disassembly (e.g. Dstn and Pex14) and regulation of growth (e.g. Adnp2, Epc1, and Ing4). Overall, the best targets with the highest potential for sensitizing cancer cells to radiation were Dstn and Map2k6, and the best targets for enhancing resistance to radiation were Iqgap and Vcan. Hence, we provide compelling evidence that screening mutant ESCs is a powerful approach to identify genes that alter radiation response. Ultimately, this knowledge can be used to define genetic variants or therapeutic targets that will enhance clinical therapy.