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A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells

ABSTRACT: A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells

PROVIDER: PRJNA643829 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12147712_1.fastq.gz	Fastqsanger.gz
	SRR12147712_2.fastq.gz	Fastqsanger.gz
	SRR12147713_1.fastq.gz	Fastqsanger.gz
	SRR12147713_2.fastq.gz	Fastqsanger.gz
	SRR12147714_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [RNA-seq]

Project description:Heterozygous germline mutations in BRCA1 or BRCA2 predispose to breast, ovarian, as well as other cancers. The main physiological function of BRCA1 and BRCA2 is to facilitate DNA replication, by stabilising and re-starting stalled replication forks. Consequently, inactivation of either BRCA1 or BRCA2 genes leads to replication pathologies and accumulation of DNA double strand breaks. Similar to BRCA1/2 inactivation, oncogene overexpression interferes with replication and inflicts DNA damage. It remains unclear how the replication defects in the two settings differ from each other and what is their combined effect on cell viability. Here, we report that accumulation of β-catenin, an oncogene of the WNT signalling pathway, is synthetically lethal with BRCA1/2 inactivation. We identify two transcription-dependent mechanisms that mediate oncogene toxicity in the context of BRCA1/2 deficiency. Firstly, accumulation of β-catenin activates E2F-dependent transcription, which accelerates G1/S transition, thus counteracting the delayed S-phase entry caused by BRCA1/2 abrogation. This, in turn, triggers illegitimate origin firing leading to fork collapse, DNA damage and deregulation of gene expression. Secondly, we find that β-catenin accumulation suppresses transcription of CDKN1A gene encoding p21, a modulator of fork progression. Decreased replication rates represent a hallmark of BRCA2 deficiency. Through p21 downregulation, β-catenin accelerates replication fork progression in BRCA2-deficient cells, thereby inflicting DNA damage and triggering cell death. Thus, our results demonstrate that oncogene-driven premature S-phase entry and increased replication rate are lethal in the context of BRCA1/2 abrogation, which explains the mutual exclusivity between oncogene activation and BRCA1/2 gene mutations in human tumours.

2021-04-01 | GSE153735 | GEO

A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [EdU-seq]

Project description:Heterozygous germline mutations in BRCA1 or BRCA2 predispose to breast, ovarian, as well as other cancers. The main physiological function of BRCA1 and BRCA2 is to facilitate DNA replication, by stabilising and re-starting stalled replication forks. Consequently, inactivation of either BRCA1 or BRCA2 genes leads to replication pathologies and accumulation of DNA double strand breaks. Similar to BRCA1/2 inactivation, oncogene overexpression interferes with replication and inflicts DNA damage. It remains unclear how the replication defects in the two settings differ from each other and what is their combined effect on cell viability. Here, we report that accumulation of β-catenin, an oncogene of the WNT signalling pathway, is synthetically lethal with BRCA1/2 inactivation. We identify two transcription-dependent mechanisms that mediate oncogene toxicity in the context of BRCA1/2 deficiency. Firstly, accumulation of -catenin activates E2F-dependent transcription, which accelerates G1/S transition, thus counteracting the delayed S-phase entry caused by BRCA1/2 abrogation. This, in turn, triggers illegitimate origin firing leading to fork collapse, DNA damage and deregulation of gene expression. Secondly, we find that β-catenin accumulation suppresses transcription of CDKN1A gene encoding p21, a modulator of fork progression. Decreased replication rates represent a hallmark of BRCA2 deficiency. Through p21 downregulation, β-catenin accelerates replication fork progression in BRCA2-deficient cells, thereby inflicting DNA damage and triggering cell death. Thus, our results demonstrate that oncogene-driven premature S-phase entry and increased replication rate are lethal in the context of BRCA1/2 abrogation, which explains the mutual exclusivity between oncogene activation and BRCA1/2 gene mutations in human tumours.

2021-04-01 | GSE153734 | GEO

A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [EdU-seq]

Project description:A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [EdU-seq]

| PRJNA643831 | ENA

A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [RNA-seq]

Project description:A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [RNA-seq]

| PRJNA644159 | ENA

A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-04-01 | GSE153736 | GEO

Understanding BRCA1 function in INK4-RB deficient tumors

Project description:Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we have created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1 deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1 deficient breast cancers.

2021-01-27 | GSE155239 | GEO

RNAseq of Brca1-deficient mouse mammary tumors

Project description:Brca1 mutation predisposes women to early onset of breast and ovarian cancers.Through its diverse functions in DNA damage repair, cell cycle control, transcription regulation, ubiquitination and so on, BRCA1 acts as a very significant tumor suppressor and genomic safeguard. Brca1 deficiency induces severe cellular stress, when occurring in the mammary glands, it impairs the regular developmental process and eventually causes tumorigenesis due to accumulation of genome instability and other mechanisms. The Brca1-defiencient mouse mammary tumor were characterized with great tumoral heterogeneity, which is in line with the human breast cancers carrying BRCA1 mutations. Here we studied the molecular complexicity of Brca1-deficient mouse mammary tumors vie RNA sequencing.

2021-11-17 | GSE148565 | GEO

A transcription-based mechanism for oncogenic β-catenin-induced lethality in BRCA1/2-deficient cells.

Project description:BRCA1 or BRCA2 germline mutations predispose to breast, ovarian and other cancers. High-throughput sequencing of tumour genomes revealed that oncogene amplification and BRCA1/2 mutations are mutually exclusive in cancer, however the molecular mechanism underlying this incompatibility remains unknown. Here, we report that activation of β-catenin, an oncogene of the WNT signalling pathway, inhibits proliferation of BRCA1/2-deficient cells. RNA-seq analyses revealed β-catenin-induced discrete transcriptome alterations in BRCA2-deficient cells, including suppression of CDKN1A gene encoding the CDK inhibitor p21. This accelerates G1/S transition, triggering illegitimate origin firing and DNA damage. In addition, β-catenin activation accelerates replication fork progression in BRCA2-deficient cells, which is critically dependent on p21 downregulation. Importantly, we find that upregulated p21 expression is essential for the survival of BRCA2-deficient cells and tumours. Thus, our work demonstrates that β-catenin toxicity in cancer cells with compromised BRCA1/2 function is driven by transcriptional alterations that cause aberrant replication and inflict DNA damage.

| S-EPMC8363664 | biostudies-literature

RNAseq of Brca1-deficient mouse mammary tumors

Project description:RNAseq of Brca1-deficient mouse mammary tumors

| PRJNA625044 | ENA

BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair

Project description:Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage responsefactor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice, and rescues HR deficiency, as measured by hypersensitivity to PARP (polyADPribose polymerase) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA cross-link repair that is distinct from HR. Disruption of the non-homologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi Anemia pathway for ICL repair. Brca1 therefore has two separate roles in ICL repair, whereas FANCD2 provides a key activity that can not be bypassed by ablation of 53BP1 or Ku. B cells were stimulated to undergo class switch recombination in vitro. Chromatin from B cells was harvested 72 hours post-stimulation and used for RPA ChIP to study the extent of resection of DNA DSBs.

2012-09-30 | E-GEOD-35698 | biostudies-arrayexpress

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