A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [EdU-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA643831 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12137167.fastq.gz | Fastqsanger.gz | |||
| SRR12137168.fastq.gz | Fastqsanger.gz | |||
| SRR12137169.fastq.gz | Fastqsanger.gz | |||
| SRR12137170.fastq.gz | Fastqsanger.gz | |||
| SRR12137171.fastq.gz | Fastqsanger.gz |
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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
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
Project description:A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells
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Project description:A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [RNA-seq]
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Project description:This SuperSeries is composed of the SubSeries listed below.
2021-04-01 | GSE153736 | GEO
Project description:Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease characterized by its aggressive nature and resistance to anti-androgen therapies. Although PARP inhibitors (PARPis) have brought new hope for mCRPC patients with homologous recombination (HR) deficient, such as those lacking BRCA1/2, the utility of PARPi monotherapy is significantly restricted, with only 10%-15% of mCRPC patients with BRCA1/2 deficiencies achieving clinical benefit. Thus, there is a critical need for innovative therapeutic strategies for mCRPC patients without BRCA deficiency. In our current study, we elucidate the pivotal role of the ATM-TRMT10A-BRCA1 axis in mediating HR repair and PARPi resistance in mCRPC. We demonstrate that TRMT10A is phosphorylated at S28 by ATM after DNA damage. This phosphorylation is essential for the recruitment of BRCA1 to sites of DNA damage, thereby facilitating HR repair. Deletion of TRMT10A compromises HR repair, rendering tumor cells more sensitive to PARPi. Importantly, we show that TRMT10A expression is upregulated in mCRPC and is modulated by Ubiquitin Specific Peptidase 10 (USP10). Inhibition of USP10 with small molecular inhibitor Spautin-1 leads to TRMT10A degradation and enhances the sensitivity of tumors to PARPi in both cell-derived xenografts (CDX) and patient-derived xenografts (PDX). Our findings underscore the vital role of ATM-TRMT10A-BRCA1 axis in the vulnerability to PARP inhibitors and introduce a promising strategy perspective for exploring synthetic lethality. This approach, which involves the combination of PARP and USP10 inhibitors, could extend therapeutic benefits to a broader group of mCRPC patients without BRCA mutation.
2024-12-30 | PXD059301 |
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.
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Project description:Mechanism of Oncogene Addiction
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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
Project description:Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223-3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.
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