Targeting homologous recombination in Notch-driven C. elegans stem cell and human tumors Journal Article


Authors: Deng, X.; Michaelson, D.; Tchieu, J.; Cheng, J.; Rothenstein, D.; Feldman, R.; Lee, S. G.; Fuller, J.; Haimovitz-Friedman, A.; Studer, L.; Powell, S.; Fuks, Z.; Hubbard, E. J. A.; Kolesnick, R.
Article 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. © 2015 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: controlled study; gene mutation; nonhuman; cancer radiotherapy; mitosis; phenotype; mammalia; homologous recombination; dna repair; wild type; cancer model; stem cell; dna strand breakage; dna; tumor cell; radiosensitivity; cell cycle g2 phase; cell cycle m phase; caenorhabditis elegans; cancer control; sequence homology; temperature sensitivity; notch1 receptor; radiation protection; nematode; glucagon like peptide 1 receptor; human; article
Journal Title: PLoS ONE
Volume: 10
Issue: 6
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2015-06-29
Start Page: e0127862
Language: English
DOI: 10.1371/journal.pone.0127862
PROVIDER: scopus
PMCID: PMC4485896
PUBMED: 26120834
DOI/URL:
Notes: Erratum issued, see DOI: 10.1371/journal.pone.0141673 -- Export Date: 2 September 2015 -- Source: Scopus
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MSK Authors
  1. Simon Nicholas Powell
    168 Powell
  2. Zvi Fuks
    309 Fuks
  3. Lorenz Studer
    154 Studer
  4. Richard N Kolesnick
    235 Kolesnick
  5. Xinzhu Deng
    10 Deng
  6. Jin Cheng
    5 Cheng
  7. Jason Hung Tchieu
    11 Tchieu
  8. John David Fuller
    7 Fuller
  9. Sang Gyu   Lee
    7 Lee