title: WRN translocation from nucleolus to nucleoplasm is regulated by SIRT1 and required for DNA repair and the development of chemoresistance.
abstract: 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.
authors: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 680-749, Republic of Korea.
authors: Sun-Young
authors: SY
authors: Lee
authors: Department of Life Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors: Hyunwoo
authors: H
authors: Lee
authors: Department of Life Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors: Eun-Sun
authors: ES
authors: Kim
authors: Department of Life Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors: Sojin
authors: S
authors: Park
authors: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 680-749, Republic of Korea.
authors: Jiyoen
authors: J
authors: Lee
authors: Department of Life Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea. Electronic address: bbccahn@mail.ulsan.ac.kr.
authors: Byungchan
authors: B
authors: Ahn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D020552:Comet Assay; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D000071657:Werner Syndrome Helicase
chemical_list: D000970:Antineoplastic Agents; D049452:Green Fluorescent Proteins; D005090:Exodeoxyribonucleases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D002945:Cisplatin
keywords: Chemoresistance; Cisplatin; DNA damage; DNA repair; SIRT1; WRN