[HTML][HTML] Targeting Homologous Recombination in Notch-Driven C. elegans Stem Cell and Human Tumors
X Deng, D Michaelson, J Tchieu, J Cheng… - PLoS …, 2015 - journals.plos.org
X Deng, D Michaelson, J Tchieu, J Cheng, D Rothenstein, R Feldman, S Lee, J Fuller…
PLoS One, 2015•journals.plos.orgMammalian 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 …
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 …
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.
PLOS