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