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The Werner's syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds.沃纳综合征4330T>C（Cys1367Arg）基因变异不影响拓扑异构酶抑制剂和铂类化合物的体外细胞毒性。
Cancer Chemother Pharmacol. 2009 Apr;63(5):881-7. doi: 10.1007/s00280-008-0793-8. Epub 2008 Aug 2.
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Werner's syndrome lymphoblastoid cells are hypersensitive to topoisomerase II inhibitors in the G2 phase of the cell cycle.维尔纳综合征淋巴母细胞样细胞在细胞周期的G2期对拓扑异构酶II抑制剂高度敏感。
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Biogerontology. 2012 Feb;13(1):49-62. doi: 10.1007/s10522-011-9341-8. Epub 2011 Jul 24.
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Mol Biol Cell. 2001 Aug;12(8):2412-21. doi: 10.1091/mbc.12.8.2412.
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Functional role of the Werner syndrome RecQ helicase in human fibroblasts.Werner综合征RecQ解旋酶在人成纤维细胞中的功能作用。
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Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle.沃纳综合征蛋白在细胞周期S期复制停滞和DNA损伤后，以ATR/ATM依赖的方式被磷酸化。
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WRN helicase defective in the premature aging disorder Werner syndrome genetically interacts with topoisomerase 3 and restores the top3 slow growth phenotype of sgs1 top3.在早老性疾病沃纳综合征中存在缺陷的WRN解旋酶与拓扑异构酶3发生基因相互作用，并恢复了sgs1 top3的top3生长缓慢表型。
Aging (Albany NY). 2009 Feb 5;1(2):219-33. doi: 10.18632/aging.100020.

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Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study.基于人群的化学物质体外危害和浓度-反应评估：千人基因组高通量筛选研究
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Predictive impact of genetic polymorphisms in DNA repair genes on susceptibility and therapeutic outcomes to colorectal cancer patients.DNA修复基因中的遗传多态性对结直肠癌患者易感性和治疗结果的预测影响。
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Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach.利用全基因组方法鉴定导致顺铂诱导细胞毒性的基因变异。
Am J Hum Genet. 2007 Sep;81(3):427-37. doi: 10.1086/519850. Epub 2007 Aug 1.
2
WRN functions in a RAD18-dependent damage avoidance pathway.WRN在一条依赖RAD18的损伤规避途径中发挥作用。
Biol Pharm Bull. 2007 Jun;30(6):1080-3. doi: 10.1248/bpb.30.1080.
3
The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging.细胞衰老在沃纳综合征中的作用：迈向人类早衰的治疗干预
Ann N Y Acad Sci. 2007 Apr;1100:455-69. doi: 10.1196/annals.1395.051.
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Mechanisms of resistance to cisplatin and carboplatin.顺铂和卡铂的耐药机制。
Crit Rev Oncol Hematol. 2007 Jul;63(1):12-31. doi: 10.1016/j.critrevonc.2007.02.001. Epub 2007 Mar 1.
5
WRN counteracts the NHEJ pathway upon camptothecin exposure.在喜树碱暴露时，WRN会对抗非同源末端连接途径。
Biochem Biophys Res Commun. 2007 Apr 6;355(2):477-82. doi: 10.1016/j.bbrc.2007.01.175. Epub 2007 Feb 7.
6
Effect of population and gender on chemotherapeutic agent-induced cytotoxicity.人群和性别对化疗药物诱导的细胞毒性的影响。
Mol Cancer Ther. 2007 Jan;6(1):31-6. doi: 10.1158/1535-7163.MCT-06-0591.
7
Molecular mechanisms of resistance and toxicity associated with platinating agents.与铂类药物相关的耐药性和毒性的分子机制。
Cancer Treat Rev. 2007 Feb;33(1):9-23. doi: 10.1016/j.ctrv.2006.09.006. Epub 2006 Nov 3.
8
Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity.参与DNA双链断裂修复途径的基因多态性与苯诱导的血液毒性易感性
Carcinogenesis. 2006 Oct;27(10):2083-9. doi: 10.1093/carcin/bgl061. Epub 2006 May 25.
9
Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer.人类癌症中早老性韦尔纳综合征基因的表观遗传失活
Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8822-7. doi: 10.1073/pnas.0600645103. Epub 2006 May 24.
10
Impact of genetic variations in the WRN gene on age related pathologies and mortality.WRN基因中的遗传变异对与年龄相关的病理状况和死亡率的影响。
Mech Ageing Dev. 2006 Mar;127(3):307-13. doi: 10.1016/j.mad.2005.11.005. Epub 2006 Jan 6.

沃纳综合征4330T>C（Cys1367Arg）基因变异不影响拓扑异构酶抑制剂和铂类化合物的体外细胞毒性。

The Werner's syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds.

作者信息

Innocenti Federico, Mirkov Snezana, Nagasubramanian Ramamoorthy, Ramírez Jacqueline, Liu Wanqing, Bleibel Wasim K, Shukla Sunita J, Hennessy Kathleen, Rosner Gary L, Cook Edwin, Eileen Dolan M, Ratain Mark J

机构信息

Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637, USA.

出版信息

Cancer Chemother Pharmacol. 2009 Apr;63(5):881-7. doi: 10.1007/s00280-008-0793-8. Epub 2008 Aug 2.

DOI:10.1007/s00280-008-0793-8
PMID:18677484
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2731557/
Abstract

PURPOSE

Werner's syndrome (WS) is a recessive disorder of premature onset of processes associated with aging. Defective DNA repair has been reported after exposure of cells isolated from WS patients to DNA-damaging agents. The germline 4330T>C (Cys1367Arg) variant in the WS gene (WRN) has been associated with protection from age-related diseases, suggesting it has a functional role. We studied whether the 4330T>C variant confers altered drug sensitivity in vitro.

METHODS

4330T>C was genotyped in 372 human lymphoblastoid cell lines (LCLs) from unrelated healthy Caucasian individuals using a TaqMan-based method. The study was powered to detect the effect of the 4330T>C genotypes after exposure to camptothecin (based upon preliminary data). The effect of the 4330T>C variant on the cytotoxicity of etoposide, carboplatin, cisplatin and daunorubicin was also tested. WRN expression in 57 LCLs was measured by microarray.

RESULTS

No significant difference between the IC50 of the cells was observed among genotypes (P = 0.46) after exposure to camptothecin. No association was also observed for etoposide, carboplatin, cisplatin, and daunorubicin (ANOVA, P > 0.05). WRN expression also did not vary across genotypes (ANOVA, P = 0.37).

CONCLUSION

These results suggest that this nonsynonymous variant has relatively normal function at the cellular level.

摘要

目的

沃纳综合征（WS）是一种与衰老相关的过早发病的隐性疾病。据报道，从WS患者分离的细胞暴露于DNA损伤剂后，DNA修复存在缺陷。WS基因（WRN）中的种系4330T>C（Cys1367Arg）变体与预防年龄相关疾病有关，表明它具有功能作用。我们研究了4330T>C变体在体外是否会导致药物敏感性改变。

方法

使用基于TaqMan的方法对372例来自无关健康白种人的人淋巴母细胞系（LCL）进行4330T>C基因分型。该研究旨在检测暴露于喜树碱后4330T>C基因型的影响（基于初步数据）。还测试了4330T>C变体对依托泊苷、卡铂、顺铂和柔红霉素细胞毒性的影响。通过微阵列测量57个LCL中的WRN表达。

结果

暴露于喜树碱后，各基因型之间细胞的半数抑制浓度（IC50）未观察到显著差异（P = 0.46）。对于依托泊苷、卡铂、顺铂和柔红霉素也未观察到关联（方差分析，P > 0.05）。WRN表达在各基因型之间也没有变化（方差分析，P = 0.37）。

结论

这些结果表明，这种非同义变体在细胞水平上具有相对正常的功能。