p53 isoform Delta 113p53/ Delta 133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage

• Published in: Cell research 2015-03, Vol.25 (3), p.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: Article
• Language: English
• Subjects: Danio rerio
• ISSN: 1001-0602
• DOI: 10.1038/cr.2015.22

The inhibitory role of p53 in DNA double-strand break (DSB) repair seems contradictory to its tumor-suppressing property. The p53 isoform Delta 113p53/ Delta 133p53 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 Delta 113p53 expression is strongly induced by gamma -irradiation, but not by UV-irradiation or heat shock treatment. Strikingly, Delta 113p53 promotes DNA DSB repair pathways, including homologous recombination, non-homologous end joining and single-strand annealing. To study the biological significance of Delta 113p53 in promoting DNA DSB repair, we generated a zebrafish Delta 113p53 super(M/M) mutant via the transcription activator-like effector nuclease technique and found that the mutant is more sensitive to gamma -irradiation. The human ortholog, Delta 133p53, is also only induced by gamma -irradiation and functions to promote DNA DSB repair. Delta 133p53-knockdown cells were arrested at the G2 phase at the later stage in response to gamma -irradiation due to a high level of unrepaired DNA DSBs, which finally led to cell senescence. Furthermore, Delta 113p53/ Delta 133p53 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 Delta 113p53/ Delta 133p53 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 Delta 133p53 expression in normal cells or tissues provides an important tolerance marker for cancer patients to radiotherapy.