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

摘要

DNA double-strand breaks (DSBs) are deleteriousand tumorigenic but could also be essential forDNA-based processes. Yet the landscape of physiologicalDSBs and their role and repair are still elusive.Here, we mapped DSBs at high resolution in cancerand non-tumorigenic cells and found a transcription-coupledrepair mechanism at oncogenic superenhancers.At these super-enhancers the transcriptionfactor TEAD4, together with various transcriptionfactors and co-factors, co-localizes with the repairfactor RAD51 of the homologous recombinationpathway. Depletion of TEAD4 or RAD51 increasesDSBs at RAD51/TEAD4 common binding sites withinsuper-enhancers and decreases expression ofrelated genes, which are mostly oncogenes. Colocalizationof RAD51 with transcription factors atsuper-enhancers occurs in various cell types, suggestinga broad phenomenon. Together, our findingsuncover a coupling between transcription and repairmechanisms at oncogenic super-enhancers, to controlthe hyper-transcription of multiple cancer drivers.