Interplay between benzo(a)pyrene-induced senescence and transcriptonal repression of DNA repair
苯并芘诱导的衰老与 DNA 修复转录抑制之间的相互作用
基本信息
- 批准号:388225306
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2017
- 资助国家:德国
- 起止时间:2016-12-31 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
A coordinated and faithful DNA repair is of central importance for maintaining genomic integrity and survival. A significant influence on the outcome of DNA damage processing is expected if the relative abundance of key repair factors is altered. This could disrupt the balance between individual repair pathways and the effectiveness of the DNA repair. Transcriptional activation of DNA repair genes is an important regulatory mechanism contributing to the adaptation of cells to genotoxic stress conditions. However, it appears that the inverse strategy, i.e. downregulation of gene expression in response to DNA damage, also plays a role in the fine-tuned regulation of complex DNA repair pathways. In our previous work, we analysed the regulation of DNA repair in response to benzo(a)pyrene 9,10-diol-7,8-epoxide (BPDE), the active metabolite of benzo(a)pyrene (B[a]P), which is the most important carcinogen formed by incomplete combustion during food preparation and smoking. We showed that low (nontoxic) BPDE concentrations cause AP-1 and p53 dependent upregulation of several NER genes, leading to enhanced NER activity and consequently reducing the effectiveness of a challenge dose (adaptive response). To further elucidate alterations in the expression of DNA repair genes following BPDE exposure, qPCR microarrays were performed, revealing a strong repression of the mismatch repair factors MSH2, MSH6 and EXO1, as well as of Rad51, the central component of the homologous recombination. The repression of these genes was mediated by abrogation of the E2F1 pathway. As part of the present application, we will investigate the molecular mechanisms leading to the repression of MSH2, MSH6, EXO1 and RAD51, focussing on mechanisms underlying abrogation of the E2F1 pathway and on the impact of histone modification.Since we could show that repression of these DNA repair mechanisms is a specific trait of senescent cells, the repression may represent a great danger for the organism. In absence of these important DNA repair mechanisms, smoking induced DNA lesions, may lead to accumulation of mutations and chromosomal aberrations in senescent cells. Furthermore, since the nontoxic BPDE concentrations only induce a transient DNA damage response, the cells may exit senescence with unrepaired genomic alterations, which could contribute to the carcinogenic potential of smoking. To test this hypothesis, the mechanisms responsible for induction and maintenance of senescence will be analysed using senescent and non-senescent cells separated by FACS upon BPDE exposure. In detail, we will focus on the impact of the DNA damage response and the SASP phenotype. In addition open approaches using kinome and transcriptome profiling will be performed. Finally we will analyse whether cells can escape from B[a]P/BPDE-induced senescence and whether these cells harbour increased genomic alterations.
协调和忠实的 DNA 修复对于维持基因组完整性和生存至关重要。如果关键修复因子的相对丰度发生改变,预计会对 DNA 损伤处理的结果产生重大影响。这可能会破坏个体修复途径和 DNA 修复有效性之间的平衡。 DNA修复基因的转录激活是有助于细胞适应基因毒性应激条件的重要调节机制。然而,逆向策略,即响应 DNA 损伤而下调基因表达,似乎也在复杂 DNA 修复途径的微调中发挥着作用。在我们之前的工作中,我们分析了苯并(a)芘(B[a]P)的活性代谢物苯并(a)芘9,10-二醇-7,8-环氧化物(BPDE)对DNA修复的调节作用),是食品制备和吸烟过程中不完全燃烧形成的最重要的致癌物质。我们发现,低(无毒)的 BPDE 浓度会导致几个 NER 基因依赖于 AP-1 和 p53 的上调,导致 NER 活性增强,从而降低攻击剂量的有效性(适应性反应)。为了进一步阐明 BPDE 暴露后 DNA 修复基因表达的变化,进行了 qPCR 微阵列,揭示了错配修复因子 MSH2、MSH6 和 EXO1 以及同源重组的核心成分 Rad51 的强烈抑制。这些基因的抑制是通过消除 E2F1 途径介导的。作为本申请的一部分,我们将研究导致 MSH2、MSH6、EXO1 和 RAD51 抑制的分子机制,重点是废除 E2F1 途径的潜在机制以及组蛋白修饰的影响。这些DNA修复机制是衰老细胞的特定特征,其抑制可能对生物体构成巨大危险。如果缺乏这些重要的 DNA 修复机制,吸烟引起的 DNA 损伤可能会导致衰老细胞中突变和染色体畸变的积累。此外,由于无毒的 BPDE 浓度仅诱导短暂的 DNA 损伤反应,因此细胞可能会在未修复的基因组改变的情况下退出衰老,这可能会导致吸烟的致癌潜力。为了检验这一假设,将使用在暴露于 BPDE 后通过 FACS 分离的衰老和非衰老细胞来分析负责诱导和维持衰老的机制。详细来说,我们将重点关注 DNA 损伤反应和 SASP 表型的影响。此外,还将进行使用激酶组和转录组分析的开放方法。最后,我们将分析细胞是否可以逃避 B[a]P/BPDE 诱导的衰老,以及这些细胞是否具有增加的基因组改变。
项目成果
期刊论文数量(0)
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Professor Dr. Markus Christmann其他文献
Professor Dr. Markus Christmann的其他文献
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{{ truncateString('Professor Dr. Markus Christmann', 18)}}的其他基金
Mechanisms of O6-methylguanine induced senescence and transcriptional repression in glioblastoma cells
O6-甲基鸟嘌呤诱导胶质母细胞瘤细胞衰老和转录抑制的机制
- 批准号:
398037827 - 财政年份:2018
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Research Grants
Rolle von c-Fos in der Regulation der DNA-Reparatur und der Protektion gegenüber Genotoxinen
c-Fos 在 DNA 修复调节和基因毒素防护中的作用
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63792951 - 财政年份:2008
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Impact of HIPK2 and posttranslational p53 modification on B[a]P/BPDE induced cell death and senescence
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- 批准号:
470145176 - 财政年份:
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Research Grants
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