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.

p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage

“…1b and Supplementary Figure 4b ). It was recently shown that XPC knockdown decreases the activation of p38 after UV light 31 . Notably, we found that knockdown of CSB or XPC resulted in decreased binding of 14-3-3 to NELFE, which is in agreement with the reduced activation of p38 in these cells and suggests that the interaction is partially dependent on the DNA damage recognition by the NER machinery (Fig.…”

A unique chromosomal in‐frame deletion identified among seven XP‐C patients

“…8-oxo-guanine) (14)(15)(16). In addition to the role of XPC during DNA repair, it was, like several other NER proteins, ascertained at promotor regions of genes activated by nuclear receptors (17) and XPC was recently shown to promote p38-SAPK dependent gene expression under inflammatory conditions (18).…”

Elevated glucose increases genomic instability by inhibiting nucleotide excision repair

“…This function is independent of DNA damage and can influence the expression of hundreds of genes ( Bidon et al, 2018 ). XPC is also involved in the transcription of nuclear receptor genes, has a putative function in base excision repair, and promotes cytokine release in response to benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) adducts in DNA ( Fong et al, 2013 ; Schreck et al, 2016 ). The relative insensitivity of XPC cells to the effects of glucose ( Figs 2 and 5 ) was attributed to loss of its multiple functions.…”