In this study, the team maps genome-wide DNA double-strand breaks (DSBs) linked to transcription stress in cancer using sBLISS together
with transcription-stress markers. They show that superenhancers shape where transcription stress concentrates in the genome, revealing a
regulatory logic to these damage “hotspots.” Notably, while γH2AX is enriched at many transcription-stress sites, DSB-rich genes differ in
how strongly they are marked, separating high-turnover, actively repaired breaks from more weakly marked sites. Consistent with this,
impairing repair (preferentially increases break accumulation at highly γH2AX-marked, superenhancer-regulated genes, linking repair
dynamics to oncogenic transcription programs.
By integrating these layers, the work connects superenhancer-driven hypertranscription to DSB turnover and suggests that efficiently
repaired transcription-stress loci may be especially vulnerable to mutagenesis, highlighting a potential therapeutic vulnerability in cancers reliant on superenhancer programs.
To the paper
