期刊
ONCOTARGET
卷 6, 期 26, 页码 22575-22586出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4610
关键词
nucleotide excision repair; XPA; SIRT1; chemoresistance
资金
- National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea [1420070]
- National Research Foundation (NRF) of Republic of Korea [NRF-2011-0013804, NRF-2013-R1A2A2A04008115]
- Brain Busan 21 Project
- Korea Health Promotion Institute [1420070] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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