Werner syndrome lymphoblastoid cells are sensitive to camptothecin-induced apoptosis in S-phase.
Werner syndrome lymphoblastoid cells are sensitive to camptothecin-induced apoptosis in S-phase.
复制标题
沃纳综合征淋巴母细胞对喜树碱诱导的 S 期细胞凋亡敏感。
DOI：
10.1007/s004390050903
复制
发表时间：
1999
期刊：
影响因子：
5.3
通讯作者：
Rabinovitch,PS
中科院分区：
文献类型：
--
作者：
Poot,M;Gollahon,KA;Rabinovitch,PS
Werner综合征（WRN）是一种常染色体隐性遗传病，表现为内源性突变表型，主要是间充质癌的风险升高。在WRN患者中突变的基因编码3 ‘→5 ’ DNA解旋酶和3 ‘→5 ’外切酶活性。我们发现，在使用dna拓扑异构酶i捕获药物喜树碱治疗后，WRN和对照细胞中都出现了类似的s期阻滞；这可能是在两种细胞类型中观察到的药物暴露相关的生长抑制的原因。通过检查细胞死亡，获得了WRN和对照永生化b细胞系（LCLs）之间更清晰的表型差异。喜树碱诱导wrn缺陷lcl细胞死亡的机制似乎是通过细胞凋亡，这是一种强烈区分wrn缺陷与野生型lcl的表型。我们假设，在缺乏WRN功能的细胞中，拓扑异构酶- i - dna中间体持续存在。与DNA复制的冲突可能导致WRN的凋亡、突变率增加和癌症。
Werner Syndrome (WRN) is an autosomal recessive disorder showing an endogenous mutator phenotype in combination with an elevated risk of predominantly mesenchymal cancer. The gene mutated in WRN patients codes for 3’→5’ DNA helicase and 3’→5’ exonuclease activities. We have found similar S-phase arrest in both WRN and control cells after treatment with the DNA-topoisomerase-I-trapping drug camptothecin; this may be responsible for the drug-exposure-related growth inhibition seen in both cell types. A clearer phenotypic difference between WRN and control immortalized B-cell lines (LCLs) is obtained by examining cell death. The mechanism of camptothecin-induced cell death in WRN-deficient LCLs appears to be through apoptosis, a phenotype that strongly differentiates WRN-deficient from wild-type LCLs. We hypothesize that, in cells deficient for WRN function, a topoisomerase-I-DNA intermediate persists. Conflict with DNA replication may lead to apoptosis, increased mutation rates, and cancer in WRN.