title: Contributions of DNA repair, cell cycle checkpoints and cell death to suppressing the DNA damage-induced tumorigenic behavior of Drosophila epithelial cells.
abstract: When exposed to DNA-damaging agents, components of the DNA damage response (DDR) pathway trigger apoptosis, cell cycle arrest and DNA repair. Although failures in this pathway are associated with cancer development, the tumor suppressor roles of cell cycle arrest and apoptosis have recently been questioned in mouse models. Using Drosophila epithelial cells that are unable to activate the apoptotic program, we provide evidence that ionizing radiation (IR)-induced DNA damage elicits a tumorigenic behavior in terms of E-cadherin delocalization, cell delamination, basement membrane degradation and neoplasic overgrowth. The tumorigenic response of the tissue to IR is enhanced by depletion of Okra/DmRAD54 or spnA/DmRAD51--genes required for homologous recombination (HR) repair of DNA double-strand breaks in G2--and it is independent of the activity of Lig4, a ligase required for nonhomologous end-joining repair in G1. Remarkably, depletion of Grapes/DmChk1 or Mei-41/dATR-genes affecting DNA damage-induced cell cycle arrest in G2--compromised DNA repair and enhanced the tumorigenic response of the tissue to IR. On the contrary, DDR-independent lengthening of G2 had a positive impact on the dynamics of DNA repair and suppressed the tumorigenic response of the tissue to IR. Our results support a tumor suppressor role of apoptosis, DNA repair by HR and cell cycle arrest in G2 in simple epithelia subject to IR-induced DNA damage.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Dekanty
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Barrio
authors.affiliation: 1] Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Milán
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D063646:Carcinogenesis / Q000235:genetics / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D016195:G2 Phase; D011839:Radiation, Ionizing