title: Enhanced nucleotide excision repair capacity in lung cancer cells by preconditioning with DNA-damaging agents.
abstract: The capacity of tumor cells for nucleotide excision repair (NER) is a major determinant of the efficacy of and resistance to DNA-damaging chemotherapeutics, such as cisplatin. Here, we demonstrate that using lesion-specific monoclonal antibodies, NER capacity is enhanced in human lung cancer cells after preconditioning with DNA-damaging agents. Preconditioning of cells with a nonlethal dose of UV radiation facilitated the kinetics of subsequent cisplatin repair and vice versa. Dual-incision assay confirmed that the enhanced NER capacity was sustained for 2 days. Checkpoint activation by ATR kinase and expression of NER factors were not altered significantly by the preconditioning, whereas association of XPA, the rate-limiting factor in NER, with chromatin was accelerated. In preconditioned cells, SIRT1 expression was increased, and this resulted in a decrease in acetylated XPA. Inhibition of SIRT1 abrogated the preconditioning-induced predominant XPA binding to DNA lesions. Taking these data together, we conclude that upregulated NER capacity in preconditioned lung cancer cells is caused partly by an increased level of SIRT1, which modulates XPA sensitivity to DNA damage. This study provides some insights into the molecular mechanism of chemoresistance through acquisition of enhanced DNA repair capacity in cancer cells.
authors: Department of Biological Science, Dong-A University, Busan, Korea.
authors: Ji Ye
authors: JY
authors: Choi
authors: Department of Biological Science, Dong-A University, Busan, Korea.
authors: Jeong-Min
authors: JM
authors: Park
authors: Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Korea.
authors: Joo Mi
authors: JM
authors: Yi
authors: Department of Biological Science, Dong-A University, Busan, Korea.
authors: Sun-Hee
authors: SH
authors: Leem
authors: Department of Biological Science, Dong-A University, Busan, Korea.
authors: Tae-Hong
authors: TH
authors: Kang
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D011740:Pyrimidine Dimers / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011740:Pyrimidine Dimers; D002945:Cisplatin
keywords: SIRT1; XPA; chemoresistance; nucleotide excision repair