期刊
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
卷 774, 期 -, 页码 40-48出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2015.03.001
关键词
WRN; SIRT1; Cisplatin; DNA damage; DNA repair; Chemoresistance
资金
- National Research Foundation of Korea - Korean Government [20090094053]
- Priority Research Center Program through National Research Foundation of Korea - Ministry of Education, Science, and Technology [2009-0094050]
When defective or absent, Werner syndrome protein (WRN) causes a genetic premature aging disorder called Werner syndrome. Several studies have reported that defects in WRN function are responsible for not only progeria syndrome but also genomic instability via the deregulation of DNA repair, replication, recombination, and telomere stability. Given the importance of WRN in the repair process, we herein investigated the potential role of WRN in drug response by evaluating the DNA repair following exposure to cisplatin in human cancer cell lines. We found that the down-regulation of SIRT1 and inhibition of SIRT1 deacetylase activity blocked the translocation of WRN from the nucleolus to the nucleoplasm in response to genotoxic stresses. In addition, cells expressing low levels of WRN responded favorably to cisplatin, whereas cells expressing high levels responded poorly to cisplatin. The forced expression of WRN protein in chemosensitive cells resulted in an approximately two-fold increase in cell viability in response to cisplatin compared with vector controls and promoted DNA repair, while WRN-deficient cells accumulate unrepaired double-strand breaks following cisplatin exposure. These results suggest that WRN is regulated by SIRT1 and increased expression of WRN might be one of the determinants for the development of chemotherapeutic drug resistance. (C) 2015 Published by Elsevier B.V.
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