...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Archives of Toxicology >PARP1 protects from benzo[a]pyrene diol epoxide-induced replication stress and mutagenicity
【24h】

PARP1 protects from benzo[a]pyrene diol epoxide-induced replication stress and mutagenicity

机译：PARP1保护来自苯并[a]芘二醇环氧化物诱导的复制应力和致突变性

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Poly(ADP-ribosyl)ation (PARylation) is a complex and reversible posttranslational modification catalyzed by poly(ADP-ribose)polymerases (PARPs), which orchestrates protein function and subcellular localization. The function of PARP1 in genotoxic stress response upon induction of oxidative DNA lesions and strand breaks is firmly established, but its role in the response to chemical-induced, bulky DNA adducts is understood incompletely. To address the role of PARP1 in the response to bulky DNA adducts, we treated human cancer cells with benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE), which represents the active metabolite of the environmental carcinogen benzo[a]pyrene [B(a)P], in nanomolar to low micromolar concentrations. Using a highly sensitive LC-MS/MS method, we revealed that BPDE induces cellular PAR formation in a time- and dose-dependent manner. Consistently, PARP1 activity significantly contributed to BPDE-induced genotoxic stress response. On one hand, PARP1 ablation rescued BPDE-induced NAD(+) depletion and protected cells from BPDE-induced short-term toxicity. On the other hand, strong sensitization effects of PARP inhibition and PARP1 ablation were observed in long-term clonogenic survival assays. Furthermore, PARP1 ablation significantly affected BPDE-induced S- and G2-phase transitions. Together, these results point towards unresolved BPDE-DNA lesions triggering replicative stress. In line with this, BPDE exposure resulted in enhanced formation and persistence of DNA double-strand breaks in PARP1-deficient cells as evaluated by microscopic co-localization studies of 53BP1 and gamma H2A.X foci. Consistently, an HPRT mutation assay revealed that PARP inhibition potentiated the mutagenicity of BPDE. In conclusion, this study demonstrates a profound role of PARylation in BPDE-induced genotoxic stress response with significant functional consequences and potential relevance with regard to B[a]P-induced cancer risks.
机译：聚（ADP-核糖基）半月（酰基核糖基）是由聚（ADP-核糖）聚合酶（PARP）催化的复合物和可逆的后翻译，其促进蛋白质功能和亚细胞定位。 PARP1在诱导氧化DNA病变和链断断裂时的基因毒性应激反应的功能牢固地建立，但其在对化学诱导的反应中的作用被不完全理解。为了解决PARP1在对庞大DNA加合物的反应中的作用，我们将人癌细胞与苯并[a]芘7,8-二氢醇-9,10-环氧化（BPDE）处理过的人癌细胞，这代表了环境致癌物质的活性代谢物[a]芘[b（a）p]，以纳摩尔至低微摩尔浓度。使用高度敏感的LC-MS / MS方法，我们揭示了BPDE以时间和剂量依赖性的方式诱导细胞癌。一致地，PARP1活性显着导致BPDE诱导的遗传毒性应激反应。一方面，PARP1消融从BPDE诱导的短期毒性中获救了BPDE诱导的NAD（+）耗尽和保护细胞。另一方面，在长期克隆生存测定中观察到PARP抑制和PARP1消融的强敏化效应。此外，PARP1消融显着影响了BPDE诱导的S-和G2相转变。在一起，这些结果指向触发复制应激的未解析的BPDE-DNA病变。符合此，BPDE暴露导致PARP1缺陷细胞中DNA双链断裂的增强的形成和持续性，如通过53bp1和γh2a.x焦点的微观共定位研究评估的PARP1缺陷细胞。始终如一地，HPRT突变测定显示PARP抑制强调了BPDE的致突变性。总之，本研究表明，对BPDE诱导的遗传毒性应激反应具有显着的功能后果和潜在的相关性与B [A] P诱发的癌症风险的潜在相关性的深刻作用。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号