p53 isoform Δ113p53/Δ133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage

• Published in: Cell research Vol. 25; no. 3; pp. 351 - 369
• Main Authors: Gong, Lu, Gong, Hongjian, Pan, Xiao, Chang, Changqing, Ou, Zhao, Ye, Shengfan, Yin, Le, Yang, Lina, Tao, Ting, Zhang, Zhenhai, Liu, Cong, Lane, David P, Peng, Jinrong, Chen, Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2015; Nature Publishing Group
• Subjects: 631/337/1427/2122; 631/80/82; 692/699/67/1059/485; 692/699/67/581; Animals; Animals, Genetically Modified; Apoptosis - genetics; Biomedical and Life Sciences; Cell Biology; Cell Line; Cellular Senescence - genetics; DNA - genetics; DNA Breaks, Double-Stranded - radiation effects; DNA Ligase ATP; 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; Life Sciences; Original; original-article; Promoter Regions, Genetic - genetics; Protein Binding; Protein Isoforms - genetics; Rad51 Recombinase - biosynthesis; RNA Interference; RNA, Small Interfering; Tumor Suppressor Protein p53 - genetics; Zebrafish; Zebrafish Proteins - biosynthesis; Zebrafish Proteins - genetics; SSA; senescence; Δ113p53/Δ133p53; cell death; p53 isoform; HR; NHEJ
• DOI: 10.1038/cr.2015.22
• ISSN: 1001-0602; 1748-7838

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 Δ 113p53 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 Δ 113p53 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 Δ 133p53 expression in normal cells or tissues provides an important tolerance marker for cancer patients to radiotherapy.