Super-enhancers shape the landscape and repair dynamics of transcription-associated DNA breaks in cancer

Cancer is characterized by uncontrolled proliferation accompanied by the hypertranscription of oncogenes, leading to transcription stress, a key source of DNA double-strand breaks (DSBs) that jeopardize genomic stability. Yet, transcription stress is still underexplored. In this study, we utilized maps of DSBs identified through in-suspension break labeling in situ and sequencing (sBLISS), along with transcription stress markers, revealing that transcription stress regions coincide with the super-enhancer regulatory landscape. Notably, γH2AX mapping indicates its enrichment at transcription stress sites, while not all DSB-enriched genes show equal γH2AX marking, but those with DSBs tied to transcription stress are distinctly marked. Intriguingly, genes with high-DSBs marked by γH2AX exhibited significantly higher DSB turnover and repair than those with γH2AX-low genes, manifesting vulnerability to mutagenesis. These findings underscore super-enhancer activity as a determinant of the transcription stress landscape in cancer, posing a threat to the genomic stability of oncogenes.