title: Targeting Homologous Recombination in Notch-Driven C. elegans Stem Cell and Human Tumors.
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.
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Xinzhu
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Cell Biology, Helen L. and Martin S. Kimmel Center for Stem Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Michaelson
authors.affiliation: Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Tchieu
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Rothenstein
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Regina
authors.initials: R
authors.lastname: Feldman
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Sang-gyu
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Fuller
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
authors.affiliation: Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Simon
authors.initials: S
authors.lastname: Powell
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Fuks
authors.affiliation: Department of Cell Biology, Helen L. and Martin S. Kimmel Center for Stem Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: E Jane Albert
authors.initials: EJ
authors.lastname: Hubbard
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Kolesnick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D005260:Female; D016195:G2 Phase / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D034622:RNA Interference / Q000528:radiation effects; D011836:Radiation Tolerance / Q000528:radiation effects; D011839:Radiation, Ionizing; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; C060620:Glp-1 protein, C elegans; D051880:Receptors, Notch