title: Functional genomics screening utilizing mutant mouse embryonic stem cells identifies novel radiation-response genes.
abstract: 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.
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.
authors: Kimberly
authors: K
authors: Loesch
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.
authors: Stacy
authors: S
authors: Galaviz
authors: Department of Nuclear Engineering, Texas A&M University, College Station, Texas, United States of America.
authors: Zaher
authors: Z
authors: Hamoui
authors: Department of Nuclear Engineering, Texas A&M University, College Station, Texas, United States of America.
authors: Ryan
authors: R
authors: Clanton
authors: Department of Nuclear Engineering, Texas A&M University, College Station, Texas, United States of America; Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America; Texas A&M Institute for Preclinical Studies, Texas A&M University, College Station, Texas, United States of America.
authors: Gamal
authors: G
authors: Akabani
authors: Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas, United States of America.
authors: Michael
authors: M
authors: Deveau
authors: Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, United States of America.
authors: Michael
authors: M
authors: DeJesus
authors: Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, United States of America.
authors: Thomas
authors: T
authors: Ioerger
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.
authors: James C
authors: JC
authors: Sacchettini
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.
authors: Deeann
authors: D
authors: Wallis
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D063990:Gene Ontology; D023281:Genomics; D051379:Mice; D008810:Mice, Inbred C57BL; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D009154:Mutation