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

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Trends in genetics : TIG 2026 Vol.42(2) p. 177-191
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Hidmi O, Wei PC, Aqeilan RI

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Transcription is not only an essential cellular process but also a major source of endogenous DNA strand breaks.

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APA Hidmi O, Wei PC, Aqeilan RI (2026). Breaking the script: transcriptional addiction as a driver of genome instability in cancer.. Trends in genetics : TIG, 42(2), 177-191. https://doi.org/10.1016/j.tig.2025.10.007
MLA Hidmi O, et al.. "Breaking the script: transcriptional addiction as a driver of genome instability in cancer.." Trends in genetics : TIG, vol. 42, no. 2, 2026, pp. 177-191.
PMID 41266243 ↗

Abstract

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.

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