Targeting Homologous Recombination in Notch-Driven C. elegans Stem Cell and Human Tumors

PLoS One. 2015 Jun 29;10(6):e0127862. doi: 10.1371/journal.pone.0127862. eCollection 2015.

Abstract

Mammalian NOTCH1-4 receptors are all associated with human malignancy, although exact roles remain enigmatic. Here we employ glp-1(ar202), a temperature-sensitive gain-of-function C. elegans NOTCH mutant, to delineate NOTCH-driven tumor responses to radiotherapy. At ≤20°C, glp-1(ar202) is wild-type, whereas at 25°C it forms a germline stem cell⁄progenitor cell tumor reminiscent of human cancer. We identify a NOTCH tumor phenotype in which all tumor cells traffic rapidly to G2⁄M post-irradiation, attempt to repair DNA strand breaks exclusively via homology-driven repair, and when this fails die by mitotic death. Homology-driven repair inactivation is dramatically radiosensitizing. We show that these concepts translate directly to human cancer models.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / radiation effects
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Cycle Checkpoints / radiation effects
  • DNA Repair / radiation effects
  • Female
  • G2 Phase / radiation effects
  • Gene Knockdown Techniques
  • Homologous Recombination / genetics*
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation / genetics
  • Neoplasms, Germ Cell and Embryonal / genetics*
  • RNA Interference / radiation effects
  • Radiation Tolerance / radiation effects
  • Radiation, Ionizing
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Stem Cells / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Glp-1 protein, C elegans
  • Receptors, Notch