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

DNA double strand breaks (DSBs) are deleterious and tumorigenic but also 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 and found cell-type specific patterns with enrichment at insulators, promoters, enhancers and super-enhancers. The sequences around DSBs were enriched for the motif of TEAD transcription-factors in various cell types from mouse to human. However, the binding of TEAD4 inversely correlated with DSBs suggesting protection and indeed, depletion of TEAD4 increased DSBs around TEAD4 binding-sites. At these sites TEAD4 co-localized with AP-1 factors like JUN/FOS especially at enhancers whereas at super-enhancers TEAD4 overlapped also with the repair factor RAD51 of the homologous recombination pathway. Depletion of RAD51 increased DSBs specifically at RAD51/TEAD4 common sites and decreased the expression of related oncogenes. Interestingly, the co-localization of TEAD4/RAD51 was found in tumorigenic but not in non-tumorigenic super-enhancers.

Together, our findings uncover a novel coupling between transcription and repair specific for oncogenic super-enhancers to control the high expression of multiple cancer drivers.