Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation

被引:96
|
作者
Wim, JM
Vuillaume, M
Chrzanowska, K
Smeets, D
Sperling, K
Hall, J
机构
[1] INT AGCY RES CANC, UNIT MECHANISMS CARCINOGENESIS, F-69372 LYON 08, FRANCE
[2] CHILDRENS MEM HLTH INST, DEPT HUMAN GENET, PL-04736 WARSAW, POLAND
[3] UNIV NIJMEGEN HOSP, DEPT HUMAN GENET, NL-6500 HB NIJMEGEN, NETHERLANDS
[4] HUMBOLDT UNIV BERLIN, VIRCHOW KLINIKUM, INST HUMAN GENET, D-13353 BERLIN, GERMANY
关键词
D O I
10.1128/MCB.17.9.5016
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The functionality of the p53-mediated pathway, activated in response to DNA damage, has been assessed in primary fibroblast cell cultures and Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Nijmegen breakage syndrome (NBS) patients, This autosomal recessive disease is characterized by microcephaly, growth and mental retardation, chromosomal instability, radiosensitivity, and high cancer incidence, The recent mapping of the NBS gene to chromosome 8q21 demonstrates that NBS is genetically distinct from ataxia telangiectasia (AT), Changes in p53 protein levels were significantly reduced and delayed in all the NBS fibroblast cell cultures and lymphoblastoid cell lines examined compared to normal cultures over a 4-h period postirradiation (5 Gy). The transcriptional activation of p21(WAF1/CIP1) mRNA was also lower in 12 NBS fibroblast cultures examined. In agreement with an abrogated p53 function, NBS cells exposed to ionizing radiation show an abnormal cell cycle arrest at G(1)-S and a prolonged accumulation of cells in the G, phase, In contrast, exposure to the alkylating agent methyl methanesulfonate results in similar increases of p53 and p21(WAF1/CIP1) mRNA in both cell types, The ATM gene transcript was found to be expressed at similar levels in NBS and normal cells, whereas it was strongly reduced in the AT homozygote cells examined, These results suggest that the ATM gene product cannot substitute for that of the NBS gene in the signaling of cellular damage produced by ionizing radiation and that both are involved in the activation of p53. The suboptimal p53-mediated response could contribute to the high cancer risk and radiosensitivity seen in NBS patients.
引用
收藏
页码:5016 / 5022
页数:7
相关论文
共 50 条
  • [31] p53-mediated apoptosis is attenuated in Werner syndrome cells
    Spillare, EA
    Robles, AI
    Wang, XW
    Shen, JC
    Yu, CE
    Schellenberg, GD
    Harris, CC
    GENES & DEVELOPMENT, 1999, 13 (11) : 1355 - 1360
  • [32] Precise Gene Editing Preserves Hematopoietic Stem Cell Function Following Transient p53-Mediated DNA Damage Response
    Schiroli, Giulia
    Conti, Anastasia
    Ferrari, Samuele
    Jacob, Aurelien
    Albano, Luisa
    Beretta, Stefano
    Merelli, Ivan
    Di Micco, Raffaella
    Naldini, Luigi
    Genovese, Pietro
    MOLECULAR THERAPY, 2019, 27 (04) : 443 - 443
  • [33] A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
    Marion, Rosa M.
    Strati, Katerina
    Li, Han
    Murga, Matilde
    Blanco, Raquel
    Ortega, Sagrario
    Fernandez-Capetillo, Oscar
    Serrano, Manuel
    Blasco, Maria A.
    NATURE, 2009, 460 (7259) : 1149 - 1153
  • [34] CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response
    Emma Haapaniemi
    Sandeep Botla
    Jenna Persson
    Bernhard Schmierer
    Jussi Taipale
    Nature Medicine, 2018, 24 : 927 - 930
  • [35] DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress
    Krenzlin, Harald
    Demuth, Ilja
    Salewsky, Bastian
    Wessendorf, Petra
    Weidele, Kathrin
    Buerkle, Alexander
    Digweed, Martin
    PLOS GENETICS, 2012, 8 (03):
  • [36] ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response
    Lim, Lisha Qiu Jin
    Adler, Lital
    Hajaj, Emma
    Soria, Leandro R.
    Perry, Rotem Ben-Tov
    Darzi, Naama
    Brody, Ruchama
    Furth, Noa
    Lichtenstein, Michal
    Bab-Dinitz, Elizabeta
    Porat, Ziv
    Melman, Tevie
    Brandis, Alexander
    Aylon, Yael
    Ben-Dor, Shifra
    Orr, Irit
    Pri-Or, Amir
    Seger, Rony
    Shaul, Yoav
    Ruppin, Eytan
    Oren, Moshe
    Perez, Minervo
    Meier, Jordan
    Brunetti-Pierri, Nicola
    Shema, Efrat
    Ulitsky, Igor
    Erez, Ayelet
    Malitsky, Sergey
    Itkin, Maxim
    NATURE METABOLISM, 2024, 6 (07) : 1417 - 1417
  • [37] CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response
    Haapaniemi, Emma
    Botla, Sandeep
    Persson, Jenna
    Schmierer, Bernhard
    Taipale, Jussi
    NATURE MEDICINE, 2018, 24 (07) : 927 - +
  • [38] Outcome of the p53-mediated DNA damage response in neuroblastoma is determined by morphological subtype and MYCN expression
    Carr-Wilkinson, Jane
    Griffiths, Rebecca
    Elston, Rebecca
    Goranov, Bojidar
    Redfern, Christopher P. F.
    Gamble, Laura D.
    Lunec, John
    Tweddle, Deborah A.
    CELL CYCLE, 2011, 10 (21) : 3778 - 3787
  • [39] A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
    Rosa M. Marión
    Katerina Strati
    Han Li
    Matilde Murga
    Raquel Blanco
    Sagrario Ortega
    Oscar Fernandez-Capetillo
    Manuel Serrano
    Maria A. Blasco
    Nature, 2009, 460 : 1149 - 1153
  • [40] In mammary epithelial cells p53-mediated apoptosis in response to DNA damage is dependent on the agent and can be influenced by growth factors
    Merlo, GR
    Fiore, L
    Basolo, F
    WoodsCook, K
    Hynes, NE
    ENDOCRINE-RELATED CANCER, 1997, 4 (01) : 55 - 66