Breaking the script: transcriptional addiction as a driver of genome instability in cancer

Transcription is not only an essential cellular process but also a major source of endogenous DNA strand breaks. Many cancers exhibit transcriptional addiction and rely on dysregulated and excessive transcription to maintain the malignant state. We review recent advances in transcription-associated DNA breaks and their role as an essential player in endogenous fragility. We highlight the contrast between replication-dependent transcriptional breaks (e.g., transcription–replication conflicts) and replication-independent transcriptional breaks (resulting from transcription itself). We outline two types of transcriptional double-strand breaks (DSBs): promoter-associated breaks that are linked to gene activation, and gene-body breaks that occur stochastically from transcription byproducts. We discuss how supercoiling, R-loops, and enhancer–promoter looping at super-enhancer (SE)-regulated loci can increase DNA fragility and thereby create a distinct Achilles’ heel, and propose that targeting the coupling between SE-driven transcription and DNA repair could offer new therapeutic strategies for cancer.