ZFIN ID: ZDB-PUB-150224-18
p53 isoform Δ113p53/Δ133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage
Gong, L., Gong, H., Pan, X., Chang, C., Ou, Z., Ye, S., Yin, L., Yang, L., Tao, T., Zhang, Z., Liu, C., Lane, D.P., Peng, J., Chen, J.
Date: 2015
Source: Cell Research   25(3): 351-69 (Journal)
Registered Authors: Peng, Jinrong, Tao, Ting
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Apoptosis/genetics*
  • Cell Line
  • Cellular Senescence/genetics*
  • DNA/genetics
  • DNA Breaks, Double-Stranded/radiation effects*
  • DNA Ligases/biosynthesis
  • DNA Repair/genetics*
  • DNA-Binding Proteins/biosynthesis
  • DNA-Binding Proteins/metabolism
  • G2 Phase Cell Cycle Checkpoints/genetics
  • G2 Phase Cell Cycle Checkpoints/radiation effects
  • Humans
  • Promoter Regions, Genetic/genetics
  • Protein Binding
  • Protein Isoforms/genetics
  • RNA Interference
  • RNA, Small Interfering
  • Rad51 Recombinase/biosynthesis
  • Tumor Suppressor Protein p53/genetics*
  • Zebrafish
  • Zebrafish Proteins/biosynthesis
  • Zebrafish Proteins/genetics*
PubMed: 25698579 Full text @ Cell Res.
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ABSTRACT
The inhibitory role of p53 in DNA double-strand break (DSB) repair seems contradictory to its tumor-suppressing property. The p53 isoform Δ113p53/Δ133p53 is a p53 target gene that antagonizes p53 apoptotic activity. However, information on its functions in DNA damage repair is lacking. Here we report that Δ113p53 expression is strongly induced by γ-irradiation, but not by UV-irradiation or heat shock treatment. Strikingly, Δ113p53 promotes DNA DSB repair pathways, including homologous recombination, non-homologous end joining and single-strand annealing. To study the biological significance of Δ113p53 in promoting DNA DSB repair, we generated a zebrafish Δ113p53(M/M) mutant via the transcription activator-like effector nuclease technique and found that the mutant is more sensitive to γ-irradiation. The human ortholog, Δ133p53, is also only induced by γ-irradiation and functions to promote DNA DSB repair. Δ133p53-knockdown cells were arrested at the G2 phase at the later stage in response to γ-irradiation due to a high level of unrepaired DNA DSBs, which finally led to cell senescence. Furthermore, Δ113p53/Δ133p53 promotes DNA DSB repair via upregulating the transcription of repair genes rad51, lig4 and rad52 by binding to a novel type of p53-responsive element in their promoters. Our results demonstrate that Δ113p53/Δ133p53 is an evolutionally conserved pro-survival factor for DNA damage stress by preventing apoptosis and promoting DNA DSB repair to inhibit cell senescence. Our data also suggest that the induction of Δ133p53 expression in normal cells or tissues provides an important tolerance marker for cancer patients to radiotherapy.Cell Research advance online publication 20 February 2015; doi:10.1038/cr.2015.22.
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