Understanding and modulating interactions of the base excision repair glycosylase hOGG1 in tumorigenic gene transcription

了解和调节碱基切除修复糖基化酶 hOGG1 在致瘤基因转录中的相互作用

• 批准号: 523998827
• 负责人: Dr. Ingrid Teßmer, Ph.D.
• 金额: --
• 依托单位: Rudolf-Virchow-Zentrum - Center for Integrative and Translational Bioimaging
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/523998827?language=en
• 关键词: Understanding; modulating; interactions; base; excision

The research grant focuses on the specific interaction between the DNA repair enzyme hOGG1 and the oncogene transcription factor Myc, which we recently reported. The DNA glycosylase hOGG1 is responsible for the removal of mutagenic oxidative lesions (oxoguanines) from DNA. We showed that oxoguanine repair activity of hOGG1 is directly inactivated by interaction with Myc. This likely results in prolonged binding of hOGG1-Myc complexes on oxidative DNA lesions, where concomitant conformational changes lead to loading of Myc onto the DNA by hOGG1 at a lesion and onto its E-box recognition motif in gene promoters in close proximity of the lesion. Importantly, the interaction between hOGG1 and Myc was significantly enhanced under oxidising conditions, which can explain the observed enhanced expression of Myc target genes under oxidative stress. Myc recruitment by hOGG1 under oxidative stress in tumour cells represents likely a pathogenic process that further augments tumour growth by enhancing cytokine expression. Here, we strive to determine the biological and medical relevance and structural basis of the hOGG1-Myc interaction by expanding our single molecule methods spectrum to in vivo and crystallographic studies. Our data will lay the basis for the development of inhibitors of hOGG1-Myc interactions in tumour cells as well as contribute yet another piece to the puzzle to help us understand the intricate DNA interaction networks in our cells.

该研究经费重点关注我们最近报道的 DNA 修复酶 hOGG1 和癌基因转录因子 Myc 之间的特异性相互作用。 DNA 糖基化酶 hOGG1 负责从 DNA 中去除诱变氧化损伤（氧化鸟嘌呤）。我们发现 hOGG1 的氧代鸟嘌呤修复活性通过与 Myc 的相互作用直接失活。这可能导致 hOGG1-Myc 复合物在氧化性 DNA 损伤上的长时间结合，其中伴随的构象变化导致损伤处的 hOGG1 将 Myc 加载到 DNA 上，并加载到紧邻损伤的基因启动子中的 E-box 识别基序上。重要的是，hOGG1 和 Myc 之间的相互作用在氧化条件下显着增强，这可以解释观察到的 Myc 靶基因在氧化应激下表达增强的现象。肿瘤细胞氧化应激下 hOGG1 募集 Myc 可能代表一种致病过程，通过增强细胞因子表达进一步促进肿瘤生长。在这里，我们努力通过将我们的单分子方法范围扩展到体内和晶体学研究来确定 hOGG1-Myc 相互作用的生物学和医学相关性以及结构基础。我们的数据将为肿瘤细胞中 hOGG1-Myc 相互作用抑制剂的开发奠定基础，并为这个难题贡献另一部分，以帮助我们了解细胞中复杂的 DNA 相互作用网络。