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Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211471 | GEO | 2023/10/13

REPOSITORIES: GEO

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Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [Repli-seq]

Project description:Transcription inhibition has become an attractive strategy for anticancer therapy because many cancers arise from dysregulated transcription programs. Topoisomerase 1 (TOP1) and bromodomain containing protein 4 (BRD4) coordinate each other to regulate transcriptional elongation. Using a collection of patient-derived xenograft mouse models of pancreatic cancer we show that the combined inhibition of TOP1 and BRD4 is synergistic in arresting tumor growth. We link this effect to the ability of TOP1 and BRD4 to control pause-release, a rate-limiting step in early elongation. By comparing nascent transcripts with the recruitment of elongation and termination factors along genes, we found that combined inhibition of TOP1 and BRD4, while globally impairing RNA production, also disturbs the recruitment of proteins involved in termination. Thus, RNA polymerases stay engaged with the DNA downstream of polyadenylation sites for hundreds of kilobases leading to readthrough-transcription. Because this pervasive transcription occurs also during replication, it perturbs replisome progression leading to increased DNA damage and cell cycle arrest. The synergistic effect of TOP1 and BRD4 inhibition is specific for the tumor cells as negligible transcriptional defects are observed in non-tumor cells. This work provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors in the treatment of highly transcription- and replication-driven tumors.

2023-10-13 | GSE211470 | GEO

Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [SLAM-seq]

2023-10-13 | GSE211469 | GEO

Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [RNA-seq]

2023-10-13 | GSE211468 | GEO

Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [CAD-seq]

2023-10-13 | GSE211465 | GEO

Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [ChIP-seq]

2023-10-13 | GSE211467 | GEO

Coinhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancer via readthrough transcription.

Project description: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.

| S-EPMC10575591 | biostudies-literature

Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription

Project description:Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription

| PRJNA870461 | ENA

Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [ChIP-seq]

Project description:Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [ChIP-seq]

| PRJNA870464 | ENA

Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [RNA-seq]

Project description:Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [RNA-seq]

| PRJNA870465 | ENA

Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [CAD-seq]

Project description:Inhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills tumours by inducing readthrough transcription [CAD-seq]

| PRJNA870463 | ENA

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