title: p53 isoform Δ113p53/Δ133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage.
abstract: 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.
authors.affiliation: Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences.
authors.forename: Lu
authors.initials: L
authors.lastname: Gong
authors.affiliation: Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Gong
authors.affiliation: Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences.
authors.forename: Xiao
authors.initials: X
authors.lastname: Pan
authors.affiliation: College of Natural Resources and Environment, South China Agricultural University, Guangzhou, Guangdong 510650, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Chang
authors.affiliation: Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ou
authors.affiliation: Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences.
authors.forename: Shengfan
authors.initials: S
authors.lastname: Ye
authors.affiliation: Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences.
authors.forename: Le
authors.initials: L
authors.lastname: Yin
authors.affiliation: Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences.
authors.forename: Lina
authors.initials: L
authors.lastname: Yang
authors.affiliation: College of Animal Sciences, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhenjiang 310058, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Tao
authors.affiliation: 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.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Developmental and Stem Cell Institute, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Biomedical Research Council, Agency for Science and Technology Research, Singapore.
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.affiliation: College of Animal Sciences, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhenjiang 310058, China.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Peng
authors.affiliation: Key laboratory for Molecular Animal Nutrition, Ministry of Education, Innovation Center for Signaling Network, College of Life Sciences.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D004247:DNA / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000096:biosynthesis; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D051135:Rad51 Recombinase / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C502793:Rad52 protein, zebrafish; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C571228:tp53 protein, zebrafish; D004247:DNA; D051135:Rad51 Recombinase; D011088:DNA Ligases; D000072481:DNA Ligase ATP