Activation of Oncogenic Super-Enhancers Is Coupled with DNA Repair by RAD51

Abstract

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 specific for oncogenic super-enhancers. At these super-enhancers the transcription factor TEAD4, together with AP-1 factors like JUN and FOS, colocalize with the repair factor RAD51 of the homologous recombination pathway. Depletion of TEAD4 or RAD51 increased DSBs specifically at RAD51/TEAD4 common binding-sites within super-enhancers and decreased expression of related genes, which are mostly oncogenes. Interestingly, TEAD4/RAD51 colocalize at super-enhancers of tumorigenic- but not in non-tumorigenic cells. Together, our findings uncover a novel coupling between transcription and repair mechanisms specific for oncogenic super-enhancers, to control the high expression of multiple cancer drivers.