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

作　　者：Lu Gong Hongjian Gong Xiao Pan Changqing Chang Zhao Ou Shengfan Ye Le Yin Lina Yang Ting Tao Zhenhai Zhang Cong Liu David P Lane Jinrong Peng Jun Chen 

机构地区：[1]Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences [2]College of Animal Sciences, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhenjiang 310058, China [3]College of Natural Resources and Environment, South China Agricultural University, Guangzhou, Guangdong 510650, China [4]National Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China [5]Developmental and Stem Cell Institute, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China [6]Biomedical Research Council, Agency for Science and Technology Research, Singapore

出　　处：《Cell Research》2015年第3期351-369,共19页细胞研究（英文版）

摘　　要：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.

关 键 词：p53 isoform △113p53/△133p53 NHEJ HR SSA cell death SENESCENCE 

分 类 号：Q691[生物学—生物物理学] Q523