The landscape and consequences of transcription stress

Cancer is characterized by uncontrolled proliferation and hypertranscription of oncogenes, leading to transcription stress, a major source of DNA double-strand breaks (DSBs) that threaten genomic stability. However, the landscape and consequences of transcription stress remain incompletely understood. Here, using genome-wide maps of DSBs identified by sBLISS alongside transcription stress markers, we reveal that transcription stress regions are highly enriched at the super-enhancer (SE) regulatory landscape. Transcriptional induction through SEs markedly amplifies DSB accumulation compared to non-SE-driven transcription. γH2AX mapping revealed selective enrichment at transcription stress sites, with only a subset of DSB-enriched genes showing strong γH2AX marking. Notably, genes with high DSBs and strong γH2AX signals exhibited significantly higher DSB turnover and repair than γH2AX-low genes, correlating with increased vulnerability to mutagenesis. These findings identify SE-driven transcription as a major determinant of the transcription stress landscape in cancer and highlight a key mechanism threatening the genomic stability of oncogenes.