PUBLICATION

Ccdc94 Protects Cells from Ionizing Radiation by Inhibiting the Expression of p53

Authors
Sorrells, S., Carbonneau, S., Harrington, E., Chen, A.T., Hast, B., Milash, B., Pyati, U., Major, M.B., Zhou, Y., Zon, L.I., Stewart, R.A., Look, A.T., and Jette, C.
ID
ZDB-PUB-120907-18
Date
2012
Source
PLoS Genetics   8(8): e1002922 (Journal)
Registered Authors
Jette, Cicely A., Look, A. Thomas, Pyati, Ujwal, Stewart, Rodney A., Zhou, Yi, Zon, Leonard I.
Keywords
Embryos, Morpholino, Apoptosis, Zebrafish, Messenger RNA, Gene expression, Phenotypes, DNA repair
MeSH Terms
  • Mutation
  • Tumor Suppressor Protein p53/genetics*
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish*/embryology
  • Zebrafish*/genetics
  • Apoptosis/radiation effects
  • Animals
  • Gene Expression Regulation
  • Genes, Recessive
  • Radiation, Ionizing
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Radiation Tolerance/genetics*
  • Neurons/radiation effects
  • Embryonic Development/radiation effects
  • DNA Breaks, Double-Stranded/radiation effects*
(all 16)
PubMed
22952453 Full text @ PLoS Genet.
Abstract

DNA double-strand breaks (DSBs) represent one of the most deleterious forms of DNA damage to a cell. In cancer therapy, induction of cell death by DNA DSBs by ionizing radiation (IR) and certain chemotherapies is thought to mediate the successful elimination of cancer cells. However, cancer cells often evolve to evade the cytotoxicity induced by DNA DSBs, thereby forming the basis for treatment resistance. As such, a better understanding of the DSB DNA damage response (DSB?DDR) pathway will facilitate the design of more effective strategies to overcome chemo- and radioresistance. To identify novel mechanisms that protect cells from the cytotoxic effects of DNA DSBs, we performed a forward genetic screen in zebrafish for recessive mutations that enhance the IR?induced apoptotic response. Here, we describe radiosensitizing mutation 7 (rs7), which causes a severe sensitivity of zebrafish embryonic neurons to IR?induced apoptosis and is required for the proper development of the central nervous system. The rs7 mutation disrupts the coding sequence of ccdc94, a highly conserved gene that has no previous links to the DSB?DDR pathway. We demonstrate that Ccdc94 is a functional member of the Prp19 complex and that genetic knockdown of core members of this complex causes increased sensitivity to IR?induced apoptosis. We further show that Ccdc94 and the Prp19 complex protect cells from IR?induced apoptosis by repressing the expression of p53 mRNA. In summary, we have identified a new gene regulating a dosage-sensitive response to DNA DSBs during embryonic development. Future studies in human cancer cells will determine whether pharmacological inactivation of CCDC94 reduces the threshold of the cancer cell apoptotic response.

Genes / Markers
Figures
Figure Gallery (10 images)
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hi3174aTgTransgenic Insertion
zd1000
    Point Mutation
    zdf1
      Point Mutation
      1 - 3 of 3
      Show
      Human Disease / Model
      No data available
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      plrg1MO1-plrg1MRPHLNO
      prpf19MO1-prpf19MRPHLNO
      yju2MO1-yju2MRPHLNO
      1 - 3 of 3
      Show
      Fish
      Antibodies
      Name Type Antigen Genes Isotypes Host Organism
      Ab3-tp53monoclonalIgG1Mouse
      Ab3-tubamonoclonal
        IgG1Mouse
        1 - 2 of 2
        Show
        Orthology
        Gene Orthology
        yju2
        1 - 1 of 1
        Show
        Engineered Foreign Genes
        No data available
        Mapping
        No data available