Targeting Homologous Recombination in Notch-Driven C. elegans Stem Cell and Human Tumors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 26120834.
- Also identified by DOI 10.1371/journal.pone.0127862 and PMC identifier 4485896.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Homologous Recombination
- Neoplasms, Germ Cell and Embryonal
- Receptors, Notch
- Stem Cells