Schreck I, Grico N, Hansjosten I, Marquardt C, Bormann S, Seidel A, Kvietkova D L, Pieniazek D, Segerbäck D, Diabaté S, van der Horst G T J, Oesch-Bartlomowicz B, Oesch F, Weiss C
Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany.
Institute of Toxicology, University of Mainz, Mainz, Germany.
Oncogene. 2016 Feb 18;35(7):908-18. doi: 10.1038/onc.2015.145. Epub 2015 May 18.
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.
多环芳烃（PAHs）是环境污染物，其中许多是强效致癌物。苯并[a]芘（B[a]P）是研究最深入的PAHs之一，最终会代谢为基因毒素反式-B[a]P-7,8-二氢二醇-9,10-环氧化物（BPDE）。BPDE会引发与基因表达、细胞死亡和存活相关的应激反应。到目前为止，启动这些信号转导级联反应的潜在机制尚不清楚。在这里，我们表明BPDE诱导的DNA损伤被DNA损伤传感蛋白识别，从而诱导应激激活蛋白激酶（SAPK）p38的激活。令人惊讶的是，涉及激酶ATM和ATR的经典DNA损伤反应并不参与BPDE对p38-SAPK的激活。此外，在没有DNA链断裂的情况下也会发生p38-SAPK磷酸化的诱导。相反，p38-SAPK磷酸化的增加需要核苷酸切除修复（NER）和DNA损伤传感蛋白XPC和mHR23B。有趣的是，其他基因毒素，如顺铂（CDDP）、过氧化氢和紫外线辐射，也会增强XPC依赖的p38-SAPK磷酸化。相比之下，反式苯并[c]菲-3,4-二氢二醇-1,2-环氧化物的DNA加合物不能被NER正确识别，不会触发p38-SAPK激活。作为下游结果，促炎细胞因子白细胞介素-6的表达和分泌在体外被BPDE和CDDP诱导，在小鼠肺中被CDDP诱导，并且依赖于XPC。总之，我们描述了一种新的途径，其中NER蛋白对DNA损伤的识别特异性地导致p38-SAPK的激活，从而促进炎症基因的表达。
