A molecular mechanism of nickel (II): reduction of nucleotide excision repair activity by structural and functional disruption of p53

Nickel is a major carcinogen that is implicated in tumor development through occupational and environmental exposure. Although the exact molecular mechanisms of carcinogenesis by low-level nickel remain unclear, inhibition of DNA repair is frequently considered to be a critical mechanism of carcinogenesis. Here, we investigated whether low concentrations of nickel would affect p53-mediated DNA repair, especially nucleotide excision repair. Our results showed that nickel inhibited the promoter binding activity of p53 on the downstream gene GADD45A, as a result of the disturbance of p53 oligomerization by nickel. In addition, we demonstrated that nickel exposure trigger the reduction of GADD45A-mediated DNA repair by impairing the physical interactions between GADD45A and proliferating cell nuclear antigen or xeroderma pigmentosum G. Notably, in the GADD45A-knockdown system, the levels of unrepaired DNA photoproducts were higher than wild-type cells, elucidating the importance of GADD45A in the nickel-associated inhibition of DNA repair. These results imply that inhibition of p53-mediated DNA repair can be considered a potential carcinogenic mechanism of nickel at low concentrations.

[1]  P. Glazer,et al.  Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells , 2017, Carcinogenesis.

[2]  J. Uitti,et al.  Cancer incidence among copper smelting and nickel refining workers in Finland , 2017, American journal of industrial medicine.

[3]  G. Blandino,et al.  Oncogenic Intra-p53 Family Member Interactions in Human Cancers , 2016, Front. Oncol..

[4]  P. Simioni,et al.  Short-term exposure to high levels of air pollution (nickel) and the risk of acute unprovoked proximal deep vein thrombosis in the legs , 2016, Internal and Emergency Medicine.

[5]  Y. Seo,et al.  Integrative toxicogenomics-based approach to risk assessment of heavy metal mixtures/complexes: strategies and challenges , 2015, Molecular & Cellular Toxicology.

[6]  J. Thyssen,et al.  Occupational hand eczema caused by nickel allergy and semi‐quantified by dimethylglyoxime testing of the skin , 2015, Contact Dermatitis.

[7]  B. Schumacher,et al.  DNA repair mechanisms in cancer development and therapy , 2015, Front. Genet..

[8]  Max Costa,et al.  Toxicogenomic effect of nickel and beyond , 2014, Archives of Toxicology.

[9]  O. Gnedina,et al.  HDAC inhibitors induce apoptosis but not cellular senescence in Gadd45α-deficient E1A+Ras cells. , 2014, The international journal of biochemistry & cell biology.

[10]  S. Rajagopalan,et al.  A synergistic vascular effect of airborne particulate matter and nickel in a mouse model. , 2013, Toxicological sciences : an official journal of the Society of Toxicology.

[11]  Jong-Il Weon,et al.  Identification of molecular candidates and interaction networks via integrative toxicogenomic analysis in a human cell line following low-dose exposure to the carcinogenic metals cadmium and nickel. , 2013, Oncology reports.

[12]  Jessica L. Morse,et al.  p53 activation by Ni(II) is a HIF-1α independent response causing caspases 9/3-mediated apoptosis in human lung cells. , 2013, Toxicology and applied pharmacology.

[13]  Y. Seo,et al.  A novel role for Gadd45α in base excision repair: modulation of APE1 activity by the direct interaction of Gadd45α with PCNA. , 2013, Biochemical and biophysical research communications.

[14]  W. Boadi,et al.  Lipid peroxides and glutathione status in human progenitor mononuclear (U937) cells following exposure to low doses of nickel and copper , 2013, Drug and chemical toxicology.

[15]  Hailey A Clancy,et al.  Nickel: a pervasive carcinogen. , 2012, Future oncology.

[16]  A. Fersht,et al.  Electron microscopy studies on the quaternary structure of p53 reveal different binding modes for p53 tetramers in complex with DNA , 2010, Proceedings of the National Academy of Sciences.

[17]  G. Siegal,et al.  Replication Factor C Recruits DNA Polymerase δ to Sites of Nucleotide Excision Repair but Is Not Required for PCNA Recruitment , 2010, Molecular and Cellular Biology.

[18]  A. Andersen,et al.  Evidence of carcinogenicity in humans of water-soluble nickel salts , 2010, Journal of occupational medicine and toxicology.

[19]  G. Giglia-Mari,et al.  Coordination of dual incision and repair synthesis in human nucleotide excision repair , 2009, The EMBO journal.

[20]  Marietta Y. W. T. Lee,et al.  Sequential recruitment of the repair factors during NER: the role of XPG in initiating the resynthesis step , 2008, The EMBO journal.

[21]  A. Zhitkovich,et al.  Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium. , 2008, Chemical research in toxicology.

[22]  Y. Seo,et al.  Base excision DNA repair defect in Gadd45a-deficient cells , 2007, Oncogene.

[23]  Christof Niehrs,et al.  Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation , 2007, Nature.

[24]  K. Jan,et al.  Nickel chloride inhibits the DNA repair of UV-treated but not methyl methanesulfonate-treated chinese hamster ovary cells , 1993, Biological Trace Element Research.

[25]  M. Valko,et al.  Free radicals, metals and antioxidants in oxidative stress-induced cancer. , 2006, Chemico-biological interactions.

[26]  S. Clarkson,et al.  Suppression of UV-induced apoptosis by the human DNA repair protein XPG , 2006, Cell Death and Differentiation.

[27]  J. Błasiak,et al.  Nickel(II) Affects Poly(ADP-ribose) Polymerase-Mediated DNA Repair in Normal and Cancer Cells , 2006, Zeitschrift fur Naturforschung. C, Journal of biosciences.

[28]  T. Yoshimoto,et al.  The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library , 2005, Oncogene.

[29]  V. Tron,et al.  Loss of p21WAF1/Cip1 in Gadd45-deficient keratinocytes restores DNA repair capacity. , 2005, Carcinogenesis.

[30]  T. Ørntoft,et al.  DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis , 2005, Nature.

[31]  M. Tang,et al.  Nickel (II) enhances benzo[a]pyrene diol epoxide-induced mutagenesis through inhibition of nucleotide excision repair in human cells: a possible mechanism for nickel (II)-induced carcinogenesis. , 2003, Carcinogenesis.

[32]  J. Milner,et al.  p53 is a chromatin accessibility factor for nucleotide excision repair of DNA damage , 2003, The EMBO journal.

[33]  A. Hartwig,et al.  Mechanism of nickel assault on the zinc finger of DNA repair protein XPA. , 2003, Chemical Research in Toxicology.

[34]  K. Salnikow,et al.  Nickel carcinogenesis. , 1968, Mutation research.

[35]  A. Hartwig,et al.  Interference by toxic metal ions with DNA repair processes and cell cycle control: molecular mechanisms. , 2002, Environmental health perspectives.

[36]  Todd L Davidson,et al.  The role of hypoxia-inducible signaling pathway in nickel carcinogenesis. , 2002, Environmental health perspectives.

[37]  E. Denkhaus,et al.  Nickel essentiality, toxicity, and carcinogenicity. , 2002, Critical reviews in oncology/hematology.

[38]  A. Fornace,et al.  Dimethylbenzanthracene carcinogenesis in Gadd45a-null mice is associated with decreased DNA repair and increased mutation frequency. , 2001, Cancer research.

[39]  P. Hanawalt,et al.  p53-Mediated DNA Repair Responses to UV Radiation: Studies of Mouse Cells Lacking p53, p21, and/orgadd45 Genes , 2000, Molecular and Cellular Biology.

[40]  E. Paleček,et al.  Effect of transition metals on binding of p53 protein to supercoiled DNA and to consensus sequence in DNA fragments , 1999, Oncogene.

[41]  X. Wang,et al.  Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45 , 1999, Oncogene.

[42]  Y. Seo,et al.  Effect of p53 tumor suppressor on nucleotide excision repair in human colon carcinoma cells treated with 4-nitroquinoline 1-oxide. , 1999, Research Communications in Molecular Pathology and Pharmacology.

[43]  J. Healy,et al.  An in vitro study of the use of chelating agents in cleaning nickel‐contaminated human skin: an alternative approach to preventing nickel allergic contact dermatitis , 1998 .

[44]  W. El-Deiry,et al.  Regulation of p53 downstream genes. , 1998, Seminars in cancer biology.

[45]  H. Sakamoto,et al.  Phosphorylation of serine 392 stabilizes the tetramer formation of tumor suppressor protein p53. , 1997, Biochemistry.

[46]  J. T. Reardon,et al.  The Non-catalytic Function of XPG Protein during Dual Incision in Human Nucleotide Excision Repair* , 1997, The Journal of Biological Chemistry.

[47]  A. Hartwig,et al.  Induction and repair inhibition of oxidative DNA damage by nickel(II) and cadmium(II) in mammalian cells. , 1997, Carcinogenesis.

[48]  P. O'Connor,et al.  Involvement of the p53 tumor suppressor in repair of u.v.-type DNA damage. , 1995, Oncogene.

[49]  J. Saurat,et al.  Nickel and skin irritants up-regulate tumor necrosis factor-alpha mRNA in keratinocytes by different but potentially synergistic mechanisms. , 1995, International immunology.

[50]  S. Friend,et al.  Characterization of human Gadd45, a p53-regulated protein. , 1994, The Journal of biological chemistry.

[51]  P. O'Connor,et al.  Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. , 1994, Science.

[52]  A. Hartwig,et al.  Nickel(II) interferes with the incision step in nucleotide excision repair in mammalian cells. , 1994, Cancer research.

[53]  R. Metcalf,et al.  Altered p53 gene structure and expression in human epithelial cells after exposure to nickel. , 1992, Cancer research.

[54]  Chromium, nickel and welding. , 1990, IARC monographs on the evaluation of carcinogenic risks to humans.

[55]  P. Grandjean.  Human exposure to nickel. , 1984, IARC scientific publications.