Poot M, Gollahon K A, Rabinovitch P S
Department of Pathology, University of Washington, Seattle 98195-7705, USA.
Hum Genet. 1999 Jan;104(1):10-4. doi: 10.1007/s004390050903.
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.
沃纳综合征（WRN）是一种常染色体隐性疾病，表现出内源性突变体表型，同时主要间充质癌的风险升高。WRN患者中发生突变的基因编码3'→5'DNA解旋酶和3'→5'核酸外切酶活性。在用DNA拓扑异构酶-I捕获药物喜树碱处理后，我们在WRN细胞和对照细胞中均发现了类似的S期停滞；这可能是两种细胞类型中出现的与药物暴露相关的生长抑制的原因。通过检查细胞死亡情况，可以更清楚地了解WRN和对照永生化B细胞系（LCL）之间的表型差异。喜树碱诱导的WRN缺陷型LCL细胞死亡机制似乎是通过凋亡，这一表型将WRN缺陷型LCL与野生型LCL强烈区分开来。我们推测，在WRN功能缺陷的细胞中，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细胞发生凋亡、突变率增加和癌症。
