Journal Article (Review Article)

DKFZ-2025-02586

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Breaking the script: transcriptional addiction as a driver of genome instability in cancer.

Hidmi, O. ; Wei, P.-C.DKFZ* ; Aqeilan, R. I.

2026
Elsevier Science Amsterdam [u.a.]

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.

Keyword(s): DNA double-strand breaks (DSBs) ; replication stress ; super-enhancers (SEs) ; transcription stress ; transcription-associated DNA damage ; transcriptional addiction ; transcriptional hyperactivity ; transcription–replication conflicts (TRCs)

Note: 2026 Feb;42(2):177-191

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Contributing Institute(s):

1. NWG Hirngenom-Mosaizismus und Tumorgenese (B400)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; BIOSIS Reviews Reports And Meetings ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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