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

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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.