Role of poly(ADP-ribose) glycohydrolase in the regulation of cell fate in response to benzo(a)pyrene

• Published in: Experimental cell research 2012-03, Vol.318 (5), p.682-690
• Main Authors: Huang, Hai-Yan, Cai, Jian-Feng, Liu, Qing-Cheng, Hu, Gong-Hua, Xia, Bo, Mao, Ji-Yan, Wu, De-Sheng, Liu, Jian-Jun, Zhuang, Zhi-Xiong
• Format: Article
• Language: English
• Subjects: Apoptosis; Ataxia Telangiectasia Mutated Proteins; Benzo(a)pyrene (BaP); Benzo(a)pyrene - pharmacology; Cell Cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell death; Cell Line; Cell Survival; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; DNA damage; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression; Gene Knockdown Techniques; Genomic Instability; Genotype & phenotype; Glycoside Hydrolases - genetics; Glycoside Hydrolases - metabolism; Humans; Mutagens - pharmacology; Poly Adenosine Diphosphate Ribose - biosynthesis; Poly(ADP-ribose) (PAR); Poly(ADP-ribose) glycohydrolase (PARG); Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RNA Interference; Stress analysis; Toxicity; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2012.01.007

Poly(ADP-ribosyl)ation is a crucial regulator of cell fate in response to genotoxic stress. Poly(ADP-ribosyl)ation plays important roles in multiple cellular processes, including DNA repair, chromosomal stability, chromatin function, apoptosis, and transcriptional regulation. Poly(ADP-ribose) (PAR) degradation is carried out mainly by poly(ADP-ribose) glycohydrolase (PARG) enzymes. Benzo(a)pyrene (BaP) is a known human carcinogen. Previous studies in our laboratory demonstrated that exposure to BaP caused a concentration-dependent DNA damage in human bronchial epithelial (16HBE) cells. The role of PARG in the regulation of DNA damage induced by BaP is still unclear. To gain insight into the function of PARG and PAR in response to BaP, we used lentiviral gene silencing to generate 16HBE cell lines with stably suppressed PARG, and determined parameters of cell death and cell cycle following BaP exposure. We found that PARG was partially dependent on PAR synthesis, PARG depletion led to PAR accumulation. BaP-induced cell death was regulated by PARG, the absence of which was beneficial for undamaged cells. Our results further suggested that PARG probably has influence on ATM/p53 pathway and metabolic activation of BaP. Experimental evidences provided from this study suggest significant preventive properties of PAR accumulation in the toxicity caused by BaP.