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
Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences.
College of Natural Resources and Environment, South China Agricultural University, Guangzhou, Guangdong 510650, China.
Cell Res. 2015 Mar;25(3):351-69. doi: 10.1038/cr.2015.22. Epub 2015 Feb 20.
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.
p53在DNA双链断裂（DSB）修复中的抑制作用似乎与其肿瘤抑制特性相矛盾。p53亚型Δ113p53/Δ133p53是一个拮抗p53凋亡活性的p53靶基因。然而，关于其在DNA损伤修复中的功能信息尚缺。在此我们报告，Δ113p53的表达在γ射线照射后被强烈诱导，但紫外线照射或热休克处理后则不然。令人惊讶的是，Δ113p53促进DNA DSB修复途径，包括同源重组、非同源末端连接和单链退火。为研究Δ113p53在促进DNA DSB修复中的生物学意义，我们通过转录激活样效应核酸酶技术构建了斑马鱼Δ113p53(M/M)突变体，发现该突变体对γ射线照射更敏感。人类直系同源物Δ133p53也仅在γ射线照射后被诱导，并发挥促进DNA DSB修复的作用。由于高水平的未修复DNA DSB，Δ133p53敲低的细胞在γ射线照射后期停滞于G2期，最终导致细胞衰老。此外，Δ113p53/Δ133p53通过结合修复基因rad51、lig4和rad52启动子中的新型p53反应元件上调其转录，从而促进DNA DSB修复。我们的结果表明，Δ113p53/Δ133p53是一种进化上保守的促生存因子，通过防止细胞凋亡和促进DNA DSB修复来抑制细胞衰老，从而应对DNA损伤应激。我们的数据还表明，正常细胞或组织中Δ133p53表达的诱导为癌症患者放疗提供了一个重要的耐受性标志物。
