Enhanced Sensitivity to anti-Benzo(a)pyrene-diol-epoxide DNA Damage Correlates with Decreased Global Genomic Repair Attributable to Abrogated p53 Function in Human Cells

作者: Mohammed El-Mahdy , Sundaresan Venkatachalam , Qianzheng Zhu , Manzoor A. Wani , Altaf A. Wani

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摘要: DNA damage from exposure to environmental chemical carcinogens and failure of repair systems eliminate these lesions the genome are considered as crucial initial steps in development of various human malignancies. Many cellular proteins are known play vital roles overcome effects damage. Among such proteins, p53 is respond by accumulating nucleus and inhibiting cell cycle progression facilitate and the maintenance genomic stability. In this study, we have investigated the role p53 protein modulating nucleotide excision of anti -benzo( a )pyrene-diol-epoxide (BPDE)-DNA adducts related using fibroblasts with normal (p53-WT) altered (p53-Mut p53-Null). Interestingly, irrespective presence or absence p53, the -BPDE dose-dependent p21 induction response was qualitatively comparable all three lines. However, cells with defective function were deficient for removal -BPDE-DNA overall genome compared to cells wild-type activity. Strand-specific analysis within individual strands gene revealed decreased repair of nontranscribed strand p53-Mut p53-Null cells. However, transcribed appeared be identical Furthermore, and p53-Null more sensitive than p53-WT displayed increased levels -BPDE-induced apoptosis. Thus, required efficient global overall genome, but not transcription-coupled actively transcribed genes. These findings indicate that inefficient potentially cytotoxic mutagenic nontranscribed strand due loss p21, might be responsible enhanced cytotoxicity apoptosis cells upon

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