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

这项研究资助的重点是DNA修复酶hOGG1与癌基因转录因子Myc之间的特异性相互作用，我们最近报道了这一研究。DNA糖基化酶hOGG1负责从DNA中去除致突变的氧化损伤（氧鸟嘌呤）。我们发现hOGG1的氧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装载到DNA上，并装载到靠近损伤的基因启动子中的E-box识别基序上。重要的是，在氧化条件下，hOGG1与Myc的相互作用显著增强，这可以解释氧化应激下Myc靶基因的表达增强。肿瘤细胞氧化应激下由hOGG1募集Myc可能是一种致病过程，通过增强细胞因子表达进一步促进肿瘤生长。在这里，我们努力通过扩展我们的单分子方法光谱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和结构基础。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，并为帮助我们理解细胞中复杂的DNA相互作用网络提供另一块拼图。

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.