ArticleScience advances2023
Coinhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancer via readthrough transcription.
Article in Science advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 14 citations in OpenAlex.
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- Integrative analysis of RNA binding proteins identifies DDX55 as a novel regulator of 3'UTR isoform diversity.Genome biology · 2025Article
- Regulatory Mechanisms and Functional Roles of Readthrough Transcripts in Tumorigenesis.International journal of molecular sciences · 2025Review
- Comprehensive resolution and classification of the Epstein Barr virus transcriptome.Nature communications · 2025Article
- Temporospatial control of topoisomerases by essential cellular processes.Current opinion in microbiology · 2024Review
- Senataxin mediates R-loop resolution on HPV episomes.Journal of virology · 2024Article
- DNA topology: A central dynamic coordinator in chromatin regulation.Current opinion in structural biology · 2024Review
- Downstream-of-gene (DoG) transcripts contribute to an imbalance in the cancer cell transcriptome.Science advances · 2024Article
- Genome-wide Mapping of Topoisomerase Binding Sites Suggests Topoisomerase 3α (TOP3A) as a Reader of Transcription-Replication Conflicts (TRC).bioRxiv : the preprint server for biology · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
25 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pancreatic carcinoma lacks effective therapeutic strategies resulting in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC affects initiation, development, and survival of this tumor type. Using patient-derived xenografts of KRAS- and MYC-driven pancreatic carcinoma, we show that coinhibition of topoisomerase 1 (TOP1) and bromodomain-containing protein 4 (BRD4) synergistically induces tumor regression by targeting promoter pause release. Comparing the nascent transcriptome with the recruitment of elongation and termination factors, we found that coinhibition of TOP1 and BRD4 disrupts recruitment of transcription termination factors. Thus, RNA polymerases transcribe downstream of genes for hundreds of kilobases leading to readthrough transcription. This occurs during replication, perturbing replisome progression and inducing DNA damage. The synergistic effect of TOP1 + BRD4 inhibition is specific to cancer cells leaving normal cells unaffected, highlighting the tumor's vulnerability to transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of transcription and replication.
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