Influence of DNA DSB repair on cell sensitivity to chloroethylating cytostatics

DNA DSB 修复对细胞对氯乙基化细胞抑制剂敏感性的影响

• 批准号: 188280051
• 负责人: Dr. Teodora Nikolova
• 金额: --
• 依托单位: Institut für Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/188280051?language=en
• 关键词: Influence; DNA; DSB; repair; cell

The main objective of this renewal application is to continue research on the role of DNA double-strand break (DSB) repair and, specifically, the role of homologous recombination in the resistance of tumour (glioblastoma) cells to chloroethylating anticancer drugs (CENU). The repair of DNA inter strand cross links (ICL) induced by CENU in proliferating cells is a complex, multistep process, which is a key node in the tumour cell resistance to this group of chemotherapeutics. The role of proteins involved in DNA damage signaling and ICL repair and the chronological order of their activation will be elucidated. According to our model, in response to CENU critical DSB are formed replication dependently during the repair process at replication forks stalled by ICL. The generated DSB are highly cytotoxic lesions whose repair is accomplished by homologous recombination (HR). Within the frame of the proposed renewal, we wish to continue our research on CENU-induced signaling, DSB repair and cell death pathways. We plan to extend our investigations with methods for down-regulation or inhibition of HR proteins and analyze the effect on the cellular sensitivity in glioblastoma cells, for which CENU are applied in therapy. In addition, we will study the effect of chronic treatment with CENU on the expression of HR proteins in glioblastoma cell lines in vitro and in xenografts in mice. The data will help to clarify the involvement of recombinational repair in the development of cellular resistance to CENU during chemotherapy.

这一新应用的主要目的是继续研究DNA双链断裂(DSB)修复的作用，特别是同源重组在肿瘤(胶质母细胞瘤)细胞对氯乙基化抗癌药物(CENU)耐药性中的作用。CENU诱导的增殖细胞DNA链间交叉连接(ICL)的修复是一个复杂的、多步骤的过程，是肿瘤细胞对该组化疗药物耐药的关键环节。参与DNA损伤信号和ICL修复的蛋白质的作用及其激活的时间顺序将被阐明。根据我们的模型，作为对CENU的响应，关键DSB在ICL停止的复制叉处的修复过程中依赖于复制而形成。产生的DSB是高度细胞毒性的损伤，其修复是通过同源重组(HR)完成的。在更新的框架内，我们希望继续研究CENU诱导的信号、DSB修复和细胞死亡途径。我们计划通过下调或抑制HR蛋白的方法来扩大我们的研究范围，并分析其对胶质母细胞瘤细胞敏感性的影响，CENU应用于治疗。此外，我们还将研究CENU对体外培养的胶质母细胞瘤细胞系和小鼠移植瘤中HR蛋白表达的影响。这些数据将有助于阐明重组修复在化疗期间细胞对CENU耐药的发生中的作用。

项目成果

DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas

• DOI: 10.1016/j.cell.2016.09.054
• 发表时间: 2016-11-17
• 期刊: CELL
• 影响因子: 64.5
• 作者: Herrtwich, Laura;Nanda, Indrajit;Triantafyllopoulou, Antigoni
• 通讯作者: Triantafyllopoulou, Antigoni

Contribution of ATM and ATR to the Resistance of Glioblastoma and Malignant Melanoma Cells to the Methylating Anticancer Drug Temozolomide

• DOI: 10.1158/1535-7163.mct-13-0136
• 发表时间: 2013-11-01
• 期刊: MOLECULAR CANCER THERAPEUTICS
• 影响因子: 5.7
• 作者: Eich, Marcus;Roos, Wynand Paul;Kaina, Bernd
• 通讯作者: Kaina, Bernd

Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs

• DOI: 10.1158/1535-7163.mct-16-0176
• 发表时间: 2016-11-01
• 期刊: MOLECULAR CANCER THERAPEUTICS
• 影响因子: 5.7
• 作者: Berte, Nancy;Piee-Staffa, Andrea;Nikolova, Teodora
• 通讯作者: Nikolova, Teodora

DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP

DNA 损伤反应可减少由膳食致癌物 PhIP 引起的有害复制应激和染色体不稳定

• DOI: 10.1093/nar/gkw791
• 发表时间: 2016
• 期刊: Nucleic Acids Research
• 影响因子: 14.9
• 作者: Mimmler M;Peter S;Kraus A;Stroh S;Nikolova T;Seiwert N;Hasselwander S;Neitzel C;Haub J;Monien B;Nicken P;Steinberg P;Shay J;Kaina B;Fahrer J
• 通讯作者: Fahrer J