The nucleotide excision repair protein XPC is essential for bulky DNA adducts to promote interleukin-6 expression via the activation of p38-SAPK

Autor: Clarissa Marquardt, S. Diabate, Iris Hansjosten, N. Grico, Ilona Schreck, Carsten Weiss, A. Seidel, D. Pieniazek, G. T. J. van der Horst, Franz Oesch, Barbara Oesch-Bartlomowicz, D. Segerbäck, Stefanie Bormann, D.L. Kvietkova
Přispěvatelé: Molecular Genetics
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Cancer Research
DNA Repair
Carcinogenesis
DNA damage
p38 mitogen-activated protein kinases
7
8-Dihydro-7
8-dihydroxybenzo(a)pyrene 9
10-oxide
Blotting
Western
Enzyme-Linked Immunosorbent Assay
Biology
Real-Time Polymerase Chain Reaction
Transfection
p38 Mitogen-Activated Protein Kinases
DNA Adducts
Mice
03 medical and health sciences
chemistry.chemical_compound
Genetics
medicine
polycyclic compounds
Animals
Humans
RNA
Small Interfering
Molecular Biology
Carcinogen
Mice
Knockout
Cisplatin
Interleukin-6
Kinase
Fibroblasts
Cell biology
DNA-Binding Proteins
Mice
Inbred C57BL
030104 developmental biology
chemistry
Carcinogens
NIH 3T3 Cells
Cancer research
Comet Assay
Signal transduction
DNA
DNA Damage
HeLa Cells
Mutagens
Signal Transduction
medicine.drug
Nucleotide excision repair
Zdroj: Oncogene, 35(7), 908-918. Nature Publishing Group
ISSN: 0950-9232
DOI: 10.1038/onc.2015.145
Popis: Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants, and many are potent carcinogens. Benzo[a]pyrene (B[a]P), one of the best-studied PAHs, is metabolized ultimately to the genotoxin anti-B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE triggers stress responses linked to gene expression, cell death and survival. So far, the underlying mechanisms that initiate these signal transduction cascades are unknown. Here we show that BPDE-induced DNA damage is recognized by DNA damage sensor proteins to induce activation of the stress-activated protein kinase (SAPK) p38. Surprisingly, the classical DNA damage response, which involves the kinases ATM and ATR, is not involved in p38-SAPK activation by BPDE. Moreover, the induction of p38-SAPK phosphorylation also occurs in the absence of DNA strand breaks. Instead, increased phosphorylation of p38-SAPK requires the nucleotide excision repair (NER) and DNA damage sensor proteins XPC and mHR23B. Interestingly, other genotoxins such as cisplatin (CDDP), hydrogen peroxide and ultraviolet radiation also enhance XPC-dependent p38-SAPK phosphorylation. In contrast, anti-benzo[c]phenanthrene-3,4-dihydrodiol-1,2-epoxide, the DNA adducts of which are not properly recognized by NER, does not trigger p38-SAPK activation. As a downstream consequence, expression and secretion of the pro-inflammatory cytokine interleukin-6 is induced by BPDE and CDDP in vitro and by CDDP in the murine lung, and depends on XPC. In conclusion, we describe a novel pathway in which DNA damage recognition by NER proteins specifically leads to activation of p38-SAPK to promote inflammatory gene expression.
Databáze: OpenAIRE
Externí odkaz: