Fuctions And Biological Significance Of P53 And P53 Isoform Δ133p53/Δ113p53 In Human Cell Line And Zebrafish

Tumor suppressor p53 could be activated upon DNA damage, causing cell cycle arrest or apoptosis to assure genome stability. However, p53 suppressed DNA double strands break (DSB) repair, seemed contradict to its anti-tumor characteristic. p53 defect contributed to tumor generation, and p53 deficient tumor cells resisted to chemical and radiation therapies.Plenty evidence showed that p53 could response upon various stress, even perform totally contradictory function according to different stress extents. The molecular mechanism was still remained unknown. Recent research demonstrated that p53 gene locus could express various p53 isoforms. They could cooperate or antagonize p53 on regulating downstream genes, but their function and biological significance still needed further research. Besides, there was not any report described the function of p53 when it activated in high temperature. This thesis answered these questions in several aspects below.1. We found Δ133p53/A113p53 could only be highly induced upon y-ray radiation, but could not be induced upon UV or high temperature. Our further study revealed Δ133p53/A113p53 could promote DNA doule-strand break (DSB) repair pathways including homologous recombination (HR), single-strand annealing (SSA) and non-homologous end joining (NHEJ), due to Δ133p53/Δ113p53 up-regulated the expression of the crucial member from each pathway on transcription level. It not only enhanced organism survival capability in severe DNA damage, but also maintained genomic stability.2. In the process of cell reprogramming, genomic DNA was undergone intense modification and space structure change. This would lead to DNA damage. We found Δ133p53 was induced during reprogramming. We also demonstrated that Δ133p53 not only largely promoted iPS efficiency, but also significantly decreased gene mutation frequency via promoting DNA DSB repair. This study provided a new approach contributing to iPS application.3. We reported Δ133p53/Δ113p53 could be highly induced under continuely low oxidative stress, and cooperated with p53 to regulate anti-oxidant genes expression under low oxidative stress. Therefore, Δ133p53/Δ113p53 could restrict ROS level and delay senescence in organism, and enhance organism live adaptation to continuous low oxidative stress.4. When we studied p53’s function in 40℃ high temperature, we surprisely revealed that p53 had the capability to promote cell and organism survival, However, p53 defect caused excessive chaperone-mediated autophagy (CMA), leading to high mortality. We found that p53 suppressed CMA via down regulating HSF1 and HSC70 expression. This study provided a potential new therpy for patients with p53 deficient tumors.Our study solved the mystery about p53 suppressing DNA DSB repair, revealed the molecular mechanism that p53 signaling pathway performed different function upon various stress. Which is the most important, we provided new theory basis for cancer therapies.