In this article, the authors synthesize recent advances showing that the “transcriptional addiction” many cancers rely on is also a major
source of endogenous DNA damage. They highlight a key conceptual distinction between replication-dependent transcription breaks (such
as transcription–replication conflicts) and replication-independent breaks that arise directly from transcription itself. The review also
proposes a useful framework separating transcriptional DSBs into promoter-associated breaks linked to gene activation and gene-body
breaks that occur as stochastic byproducts of intense transcription. Finally, the authors discuss how super-enhancers can amplify local DNA
fragility at oncogenic loci, suggesting that targeting the coupling between super-enhancer–driven transcription and DNA repair could open
new therapeutic opportunities.
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