Mapping the Breakome of Cancer Cells: What Lessons have we learned?

DNA double strand breaks (DSBs) are deleterious and tumorigenic but could also be essential for DNA-based processes. Yet, the landscape of physiological DSBs, their role and repair are still illusive. Here, we mapped DSBs at high resolution in cancer and normal cells and found a transcription-coupled repair mechanism at oncogenic super-enhancers. At these super-enhancers the transcription factor TEAD4, together with various transcription factors and co-factors, co-localizes with the repair factor RAD51 of the homologous recombination pathway. Depletion of TEAD4 or RAD51 increased DSBs at RAD51/TEAD4 common binding sites within super-enhancers and decreased expression of related genes, which are mostly oncogenes. Our data further imply that topoisomerase 1 (TOP1), but not TOP2b, is involved in RAD51-associated DSBs. Together, our findings uncover a novel coupling between transcription and repair mechanisms at oncogenic super-enhancers, to control the hyper-transcription of multiple cancer drivers.