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

• Main Authors: Idit Hazan, Jonathan Monin, Britta A.M. Bouwman, Nicola Crosetto, Rami I. Aqeilan
• Format: Article
• Language: English
• Published: Elsevier 2019-10-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719311696

Summary: DNA double-strand breaks (DSBs) are deleterious and tumorigenic but could also be essential for DNA-based processes. Yet the landscape of physiological DSBs and their role and repair are still elusive. Here, we mapped DSBs at high resolution in cancer and non-tumorigenic 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 increases DSBs at RAD51/TEAD4 common binding sites within super-enhancers and decreases expression of related genes, which are mostly oncogenes. Co-localization of RAD51 with transcription factors at super-enhancers occurs in various cell types, suggesting a broad phenomenon. Together, our findings uncover a coupling between transcription and repair mechanisms at oncogenic super-enhancers, to control the hyper-transcription of multiple cancer drivers. : By mapping physiological double-strand breaks (DSBs) of tumorigenic and non-tumorigenic cells Hazan et al. uncover a coupled transcription-repair mechanism at oncogenic super-enhancers in which RAD51 of the homologous recombination pathway plays a key role supporting the hyper-transcription of related oncogenes. Keywords: transcription, super-enhancer, BLISS, DSBs, RAD51, TEAD4, AP-1 complex (JUN/FOS)