Nucleotide Excision Repair Pathway Activity Is Inhibited by Airborne Particulate Matter (PM10) through XPA Deregulation in Lung Epithelial Cells

Abstract

Airborne particulate matter with a diameter size of ≤10 µm (PM10) is a carcinogen that contains polycyclic aromatic hydrocarbons (PAH), which form PAH–DNA adducts. However, the way in which these adducts are managed by DNA repair pathways in cells exposed to PM10 has been partially described. We evaluated the effect of PM10 on nucleotide excision repair (NER) activity and on the levels of different proteins of this pathway that eliminate bulky DNA adducts. Our results showed that human lung epithelial cells (A549) exposed to 10 µg/cm2 of PM10 exhibited PAH–DNA adducts as well as an increase in RAD23 and XPD protein levels (first responders in NER). In addition, PM10 increased the levels of H4K20me2, a recruitment signal for XPA. However, we observed a decrease in total and phosphorylated XPA (Ser196) and an increase in phosphatase WIP1, aside from the absence of XPA–RPA complex, which participates in DNA-damage removal. Additionally, an NER activity assay demonstrated inhibition of the NER functionality in cells exposed to PM10, indicating that XPA alterations led to deficiencies in DNA repair. These results demonstrate that PM10 exposure induces an accumulation of DNA damage that is associated with NER inhibition, highlighting the role of PM10 as an important contributor to lung cancer.

Particulate Matter-Induced Oxidative Stress – Recent Mechanistic Insights from In Vitro Studies

“…Overexpressing 8-Oxoguanine glycosylase (OGG1) in BEAS-2B cells counteracted PM2.5-induced disruptions, showcasing its potential protective role (Yang et al, 2015). PM10 exposure led to PAH-DNA adducts and altered NER pathway components in A549 cells, linking PM-induced DNA damage to potential carcinogenesis (Quezada-Maldonado et al, 2022). Reference PM (urban dust SRM1649 and diesel PM SRM2975) samples elicited comparable oxidative DNA damage but differed in persistence and chromosomal instability, emphasizing the role of specific particle types (Cao et al, 2022).…”

Function, drug resistance and prognostic effect of AKR1C2 in human cancer

“…The expression of AKR1C2 was increased when cells were exposed to carcinogens such as polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene, or 1-nitropyrene, which can metabolize these toxic substances into active substances that can form adducts with DNA [17,18]. If not repaired in time, the formation of DNA adducts will damage DNA and induce cell cancerization [26,27]. AKR1C2 can reduce the ROS level in cancer cells to tolerate oxidative stress and drug stimulation, ultimately reducing death [18][19][20]28].…”