p53 isoform △113p53/△133p53 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 01.03.2015
• Subjects: Deoxyribonucleic acid; DNA; DNA双链断裂; DNA损伤; Irradiation; P53; Ultraviolet radiation; 亚型; 反应元件; 断裂修复; 紫外线照射; 衰老细胞
• DOI: 10.1038/cr.2015.22
• ISSN: 1001-0602

The inhibitory role of p53 in DNA double-strand break （DSB） repair seems contradictory to its tumor-suppressing property. The p53 isoform △113p53/△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 △113p53 expression is strongly induced by T-irradiation, but not by UV-irradiation or heat shock treatment. Strikingly, △113p53 promotes DNA DSB repair pathways, including homologous recombination, non-homologous end joining and single-strand annealing. To study the biological significance of △113p53 in promoting DNA DSB repair, we generated a zebrafish △113p53M/M mutant via the transcription activator-like effector nuclease technique and found that the mutant is more sensitive to y-irradiation. The human ortholog, △133p53, is also only induced by T-irradiation and functions to promote DNA DSB repair. △133p53-knockdown cells were arrested at the G2 phase at the later stage in response to T-irradiation due to a high level of unrepaired DNA DSBs, which finally led to cell senescence. Furthermore, △113p53/△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 △113p53/△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 △133p53 expression in normal cells or tissues provides an important tolerance marker for cancer patients to radiotherapy.