title: The nucleotide excision repair protein XPC is essential for bulky DNA adducts to promote interleukin-6 expression via the activation of p38-SAPK.
abstract: 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.
authors.affiliation: Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Schreck
authors.affiliation: Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany.|Institute of Toxicology, University of Mainz, Mainz, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Grico
authors.affiliation: Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Hansjosten
authors.affiliation: Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Marquardt
authors.affiliation: Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bormann
authors.affiliation: Biochemical Institute for Environmental Carcinogens, Lurup 4, Grosshansdorf, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Seidel
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-14183 Huddinge, Sweden.
authors.forename: D L
authors.initials: DL
authors.lastname: Kvietkova
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-14183 Huddinge, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Pieniazek
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-14183 Huddinge, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Segerbäck
authors.affiliation: Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Diabaté
authors.affiliation: MGC, Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: G T J
authors.initials: GT
authors.lastname: van der Horst
authors.affiliation: Institute of Toxicology, University of Mainz, Mainz, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Oesch-Bartlomowicz
authors.affiliation: Institute of Toxicology, University of Mainz, Mainz, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Oesch
authors.affiliation: Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Weiss
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity; D020552:Comet Assay; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity; D041681:NIH 3T3 Cells; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D009153:Mutagens; D034741:RNA, Small Interfering; C501002:Xpc protein, mouse; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; C086984:XPC protein, human; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D048051:p38 Mitogen-Activated Protein Kinases