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

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

PloS one (2015-06-30)

Xinzhu Deng, David Michaelson, Jason Tchieu, Jin Cheng, Diana Rothenstein, Regina Feldman, Sang-gyu Lee, John Fuller, Adriana Haimovitz-Friedman, Lorenz Studer, Simon Powell, Zvi Fuks, E Jane Albert Hubbard, Richard Kolesnick

要旨

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.

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DAPI, for nucleic acid staining

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