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Cigarette smoke induces DNA damage and inhibits cell cycle checkpoint and DNA repair pathways
Author(s) -
Thai Philip,
Chen Daniel,
Wu Reen
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.538.2
Subject(s) - dna damage , carcinogenesis , genome instability , dna repair , cell cycle checkpoint , chek1 , microbiology and biotechnology , chemistry , cancer research , comet assay , g2 m dna damage checkpoint , cell cycle , biology , dna , cell , biochemistry , gene
Tobacco smoke is a major cause of lung cancer. Smoke's many reactive chemicals can to lead to carcinogenesis through DNA damage and genomic instability. However, how it affects the DNA damage response (DDR) pathways has not been clearly delineated. Objective To determine the mechanism of cigarette smoke induced toxicity and carcinogenesis in airway epithelial cells. Methods In vitro exposure of airway epithelial cells (A549 and HBE1) to cigarette smoke extract (CSE) induces significant DNA strand breaks as assessed by Comet Assay. However this DNA damage induced by smoke doesn't activate key DDR pathways suggesting that smoke may actively inhibit these pathways. In particular, immunoblotting reveals minimal activation of ATM (ataxia telangiectasia, mutated) and ATR (ATM and Rad3‐related) protein kinases and corresponding downstream proteins BRCA‐1 and p53 following CSE exposure. In contrast, DNA damage induced by Cisplatin, a potent anti‐cancer drug that causes DNA crosslinks, activates all of these pathways in airway epithelial cells. Conclusion We propose that cigarette smoke has a unique effect in simultaneously inducing DNA damage but also inhibiting key DDR pathways in lung cells. This suggests that smoke induced carcinogenesis is not just due to direct damage of DNA, but also inhibition of cell cycle arrest and cell death pathways to enhance propagation cells with genomic instability.