Werner syndrome diploid fibroblasts are sensitive to 4-nitroquinoline-N-oxide and 8-methoxypsoralen:: implications for the disease phenotype
Werner syndrome diploid fibroblasts are sensitive to 4-nitroquinoline-N-oxide and 8-methoxypsoralen:: implications for the disease phenotype
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DOI：
10.1096/fj.01-0906fje
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发表时间：
2002-03-01
期刊：
影响因子：
4.8
通讯作者：
Rabinovitch, PS
中科院分区：
文献类型：
--
作者：
Poot, M;Gollahon, KA;Rabinovitch, PS
维尔纳综合征 (WRN) 的临床表型包括加速衰老以及肉瘤和其他间质来源肿瘤发病率增加的特征。该综合征是由 WRN DNA 解旋酶/核酸外切酶基因突变引起的。我们发现，与 WRN 丰富的细胞相比，WRN 缺陷的原代成纤维细胞以及类淋巴母细胞系 (LCL) 对 4-硝基喹啉-N-氧化物 (4NQO) 和 8-甲氧基补骨脂素 (8MOP) 的反应表现出增殖存活率降低。这是首次证明 WRN 患者间充质来源的原代细胞对药物过敏。值得注意的是，8MOP 诱导的 DNA 链间交联，而不是 8MOP 单加合物，在 WRN 缺陷的 LCL 中产生 S 期细胞凋亡。相反，8MOP不会诱导WRN缺陷的二倍体成纤维细胞的S期细胞凋亡，其中药物过敏完全是由于细胞增殖减少所致。 WRN 患者受损间充质细胞增殖的减少可能导致早期增殖性衰老。此外，WRN 缺陷的间充质细胞在 S 期无法响应 DNA 损伤而发生凋亡，这可能会促进基因组不稳定，并有助于阐明 WRN 患者患肉瘤的风险增加。由于链间交联被认为是通过同源重组修复的，因此这些结果表明 WRN 在停滞复制叉的重组解决中发挥着重要作用。
The clinical phenotype of Werner Syndrome (WRN) includes features reminiscent of accelerated aging and an increased incidence of sarcomas and other tumors of mesenchymal origin. This syndrome results from mutations in the WRN DNA helicase/exonuclease gene. We found that WRN deficient primary fibroblasts, as well as lymphoblastoid cell lines (LCLs), show reduced proliferative survival in response to 4-nitroquinoline-N-oxide (4NQO) and 8-methoxypsoralen (8MOP), compared with WRN-proficient cells. This is the first demonstration of drug hypersensitivity in primary cells of mesenchymal origin from WRN patients. Notably, 8MOP-induced DNA interstrand crosslinks, but not 8MOP mono-adducts, produced S-phase apoptosis in WRN-deficient LCLs. In contrast, 8MOP did not induce S-phase apoptosis in WRN-deficient diploid fibroblasts, in which drug hypersensitivity was entirely due to reduced cell proliferation. Such reduced proliferation of damaged mesenchymal cells in WRN patients may lead to earlier proliferative senescence. In addition, failure of WRN-deficient mesenchymal cells to undergo apoptosis in response to DNA damage in S-phase may promote genomic instability and could help clarify the increased risk of sarcoma in WRN patients. Because interstrand crosslinks are believed to be repaired through homologous recombination, these results suggest an important role for WRN in recombinational resolution of stalled replication forks.