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Abstract: DNA double-stranded break (DSB) is one of the most catastrophic damages of genotoxic insult. Inappropriate repair of DNA DSBs results in the loss of genetic information, mutation, and the generation of harmful genomic rearrangements, which predisposes an organism to immunodeficiency, neurological damage, and cancer. The tumor repressor p53 plays a key role in DNA damage response, and has been found to be mutated in 50% of human cancer. p53, p63, and p73 are three members of the p53 gene family. Recent discoveries have shown that human p53 gene encodes at least 12 isoforms. Different p53 members and isoforms play various roles in orchestrating DNA damage response to maintain genomic integrity. This review briefly explores the functions of p53 and its isoforms in DNA DSB repair.

p53及其异构体在DNA双链断裂修复中的作用

[1]Akyüz N, Boehden GS, Süsse S, et al., 2002. DNA substrate dependence of p53-mediated regulation of double-strand break repair. Mol Cell Biol, 22(17):6306-6317.

[2]Amson R, Pece S, Lespagnol A, et al., 2011. Reciprocal repression between p53 and TCTP. Nat Med, 18(1):91-99.

[3]Anensen N, Oyan AM, Bourdon JC, et al., 2006. A distinct p53 protein isoform signature reflects the onset of induction chemotherapy for acute myeloid leukemia. Clin Cancer Res, 12(13):3985-3992.

[4]Aoubala M, Murray-Zmijewski F, Khoury MP, et al., 2011. p53 directly transactivates Δ133p53α, regulating cell fate outcome in response to DNA damage. Cell Death Differ, 18(2):248-258.

[5]Arias-Lopez C, Lazaro-Trueba I, Kerr P, et al., 2006. p53 modulates homologous recombination by transcriptional regulation of the RAD51 gene. EMBO Rep, 7(2):219-224.

[6]Arsic N, Gadea G, Lagerqvist EL, et al., 2015. The p53 isoform Δ133p53β promotes cancer stem cell potential. Stem Cell Rep, 4(4):531-540.

[7]Bernard H, Garmy-Susini B, Ainaoui N, et al., 2013. The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression. Oncogene, 32(17):2150-2160.

[8]Blander G, Kipnis J, Leal JFM, et al., 1999. Physical and functional interaction between p53 and the Werner’s syndrome protein. J Biol Chem, 274(41):29463-29469.

[9]Boehden GS, Akyüz N, Roemer K, et al., 2003. p53 mutated in the transactivation domain retains regulatory functions in homology-directed double-strand break repair. Oncogene, 22(26):4111-4117.

[10]Bourdon JC, 2007. p53 family isoforms. Curr Pharm Biotechnol, 8(6):332-336.

[11]Bourdon JC, Fernandes K, Murray-Zmijewski F, et al., 2005. p53 isoforms can regulate p53 transcriptional activity. Genes Dev, 19(18):2122-2137.

[12]Buchhop S, Gibson MK, Wang XW, et al., 1997. Interaction of p53 with the human Rad51 protein. Nucleic Acids Res, 25(19):3868-3874.

[13]Candeias MM, Hagiwara M, Matsuda M, 2016. Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis. EMBO Rep, 17(11):1542-1551.

[14]https://doi.org/10.15252/embr.201541956

[15]Chen J, Ruan H, Ng SM, et al., 2005. Loss of function of def selectively up-regulates Δ113p53 expression to arrest expansion growth of digestive organs in zebrafish. Genes Dev, 19(23):2900-2911.

[16]Chen J, Ng SM, Chang CQ, et al., 2009. p53 isoform Δ113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish. Genes Dev, 23(3):278-290.

[17]Chipuk JE, Bouchier-Hayes L, Kuwana T, et al., 2005. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science, 309(5741):1732-1735.

[18]Courtois S, Verhaegh G, North S, et al., 2002. ΔN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene, 21(44):6722-6728.

[19]Dai C, Gu W, 2010. p53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med, 16(11):528-536.

[20]de Oca Luna RM, Wagner DS, Lozano G, 1995. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature, 378(6553):203-206.

[21]Donehower LA, Harvey M, Slagle BL, et al., 1992. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature, 356(6366):215-221.

[22]Dudáš A, Chovanec M, 2004. DNA double-strand break repair by homologous recombination. Mutat Res, 566(2):131-167.

[23]Fragou A, Tzimagiorgis G, Karageorgopoulos C, et al., 2017. Increased Δ133p53 mRNA in lung carcinoma corresponds with reduction of p21 expression. Mol Med Rep, 15(4):1455-1460.

[24]Fujita K, Mondal AM, Horikawa I, et al., 2009. p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence. Nat Cell Biol, 11(9):1135-1142.

[25]Gatz SA, Wiesmuller L, 2006. p53 in recombination and repair. Cell Death Differ, 13(6):1003-1016.

[26]Gong HJ, Zhang YX, Jiang KP, et al., 2018. p73 coordinates with Δ133p53 to promote DNA double-strand break repair. Cell Death Differ, 25(6):1063-1079.

[27]Gong JG, Costanzo A, Yang HQ, et al., 1999. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature, 399(6738):806-809.

[28]Gong L, Gong HJ, Pan X, et al., 2015. p53 isoform Δ113p53/ Δ133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage. Cell Res, 25(3):351-369.

[29]Gong L, Pan X, Yuan ZM, et al., 2016. p53 coordinates with Δ133p53 isoform to promote cell survival under low-level oxidative stress. J Mol Cell Biol, 8(1):88-90.

[30]Gonzalez S, Prives C, Cordon-Cardo C, 2003. p73α regulation by Chk1 in response to DNA damage. Mol Cell Biol, 23(22):8161-8171.

[31]Hakem R, 2008. DNA-damage repair; the good, the bad, and the ugly. EMBO J, 27(4):589-605.

[32]Helton ES, Chen XB, 2007. p53 modulation of the DNA damage response. J Cell Biochem, 100(4):883-896.

[33]Hiom K, 2010. Coping with DNA double strand breaks. DNA Repair, 9(12):1256-1263.

[34]Hoh J, Jin S, Parrado T, et al., 2002. The p53MH algorithm and its application in detecting p53-responsive genes. Proc Natl Acad Sci USA, 99(13):8467-8472.

[35]Irwin M, Marin MC, Phillips AC, et al., 2000. Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature, 407(6804):645-648.

[36]Joruiz SM, Bourdon JC, 2016. p53 isoforms: key regulators of the cell fate decision. Cold Spring Harb Perspect Med, 6(8):a026039.

[37]Keimling M, Wiesmuller L, 2009. DNA double-strand break repair activities in mammary epithelial cells—influence of endogenous p53 variants. Carcinogenesis, 30(7):1260-1268.

[38]Kim S, An SS, 2016. Role of p53 isoforms and aggregations in cancer. Medicine (Baltimore), 95(26):e3993.

[39]Langheinrich U, Hennen E, Stott G, et al., 2002. Zebrafish as a model organism for the identification and characterization of drugs and genes affecting p53 signaling. Curr Biol, 12(23):2023-2028.

[40]Levine AJ, Oren M, 2009. The first 30 years of p53: growing ever more complex. Nat Rev Cancer, 9(10):749-758.

[41]Levine AJ, Hu W, Feng Z, 2006. The p53 pathway: what questions remain to be explored? Cell Death Differ, 13(6):1027-1036.

[42]Lin YL, Sengupta S, Gurdziel K, et al., 2009. p63 and p73 transcriptionally regulate genes involved in DNA repair. PLoS Genet, 5(10):e1000680.

[43]Linke SP, Sengupta S, Khabie N, et al., 2003. p53 interacts with hRAD51 and hRAD54, and directly modulates homologous recombination. Cancer Res, 63(10):2596-2605.

[44]Marcel V, Perrier S, Aoubala M, et al., 2010a. Δ160p53 is a novel N-terminal p53 isoform encoded by Δ133p53 transcript. FEBS Lett, 584(21):4463-4468.

[45]Marcel V, Vijayakumar V, Fernández-Cuesta L, et al., 2010b. p53 regulates the transcription of its delta133p53 isoform through specific response elements contained within the TP53 P2 internal promoter. Oncogene, 29(18):2691-2700.

[46]Marmorstein LY, Ouchi T, Aaronson SA, 1998. The BRCA2 gene product functionally interacts with p53 and RAD51. Proc Natl Acad Sci USA, 95(23):13869-13874.

[47]Meek DW, 2009. Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer, 9(10):714-723.

[48]Mekeel KL, Tang W, Kachnic LA, et al., 1997. Inactivation of p53 results in high rates of homologous recombination. Oncogene, 14(15):1847-1857.

[49]Mills AA, Zheng BH, Wang XJ, et al., 1999. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature, 398(6729):708-713.

[50]Moll UM, Wolff S, Speidel D, et al., 2005. Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol, 17(6):631-636.

[51]Mondal AM, Horikawa I, Pine SR, et al., 2013. p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes. J Clin Invest, 123(12):5247-5257.

[52]Moore HC, Jordan LB, Bray SE, et al., 2010. The RNA helicase p68 modulates expression and function of the Δ133 isoform(s) of p53, and is inversely associated with Δ133p53 expression in breast cancer. Oncogene, 29(49):6475-6484.

[53]Nutthasirikul N, Limpaiboon T, Leelayuwat C, et al., 2013. Ratio disruption of the Δ133p53 and TAp53 isoform equilibrium correlates with poor clinical outcome in intrahepatic cholangiocarcinoma. Int J Oncol, 42(4):1181-1188.

[54]Ohki R, Kawase T, Ohta T, et al., 2007. Dissecting functional roles of p53 N-terminal transactivation domains by microarray expression analysis. Cancer Sci, 98(2):189-200.

[55]Okorokov AL, Orlova EV, 2009. Structural biology of the p53 tumour suppressor. Curr Opin Struct Biol, 19(2):197-202.

[56]Ou Z, Yin L, Chang CQ, et al., 2014. Protein interaction between p53 and Δ113p53 is required for the anti-apoptotic function of Δ113p53. J Genet Genomics, 41(2):53-62.

[57]Pietsch EC, Sykes SM, McMahon SB, et al., 2008. The p53 family and programmed cell death. Oncogene, 27(50):6507-6521.

[58]Powell DJ, Hrstka R, Candeias M, et al., 2008. Stress-dependent changes in the properties of p53 complexes by the alternative translation product p53/47. Cell Cycle, 7(7):950-959.

[59]Romanova LY, Willers H, Blagosklonny MV, et al., 2004. The interaction of p53 with replication protein a mediates suppression of homologous recombination. Oncogene, 23(56):9025-9033.

[60]Tomasini R, Tsuchihara K, Wilhelm M, et al., 2008. TAp73 knockout shows genomic instability with infertility and tumor suppressor functions. Genes Dev, 22(19):2677-2691.

[61]Vieler M, Sanyal S, 2018. p53 isoforms and their implications in cancer. Cancers, 10(9):288.

[62]Vogelstein B, Lane D, Levine AJ, 2000. Surfing the p53 network. Nature, 408(6810):307-310.

[63]Wang XW, Tseng A, Ellis NA, et al., 2001. Functional interaction of p53 and BLM DNA helicase in apoptosis. J Biol Chem, 276(35):32948-32955.

[64]Wilhelm MT, Rufini A, Wetzel MK, et al., 2010. Isoform-specific p73 knockout mice reveal a novel role for ΔNp73 in the DNA damage response pathway. Genes Dev, 24(6):549-560.

[65]Willers H, McCarthy EE, Wu B, et al., 2000. Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control. Oncogene, 19(5):632-639.

[66]Yang AN, Walker N, Bronson R, et al., 2000. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature, 404(6773):99-103.

[67]Yoon D, Wang YZ, Stapleford K, et al., 2004. p53 inhibits strand exchange and replication fork regression promoted by human Rad51. J Mol Biol, 336(3):639-654.

[68]Zhang HB, Somasundaram K, Peng Y, et al., 1998. BRCA1 physically associates with p53 and stimulates its transcriptional activity. Oncogene, 16(13):1713-1721.