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Research Papers:

Enhanced nucleotide excision repair capacity in lung cancer cells by preconditioning with DNA-damaging agents

Ji Ye Choi, Jeong-Min Park, Joo Mi Yi, Sun-Hee Leem and Tae-Hong Kang _

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Oncotarget. 2015; 6:22575-22586. https://doi.org/10.18632/oncotarget.4610

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Abstract

Ji Ye Choi1, Jeong-Min Park1, Joo Mi Yi2, Sun-Hee Leem1, Tae-Hong Kang1

1Department of Biological Science, Dong-A University, Busan, Korea

2Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Korea

Correspondence to:

Tae-Hong Kang, e-mail: thkang@dau.ac.kr

Keywords: nucleotide excision repair, XPA, SIRT1, chemoresistance

Received: January 28, 2015     Accepted: June 20, 2015     Published: July 20, 2015

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.


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