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ABSTRACT: Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition

PROVIDER: PRJNA1218519 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32206232.fastq.gz	Fastqsanger.gz
	SRR32206232_1.fastq.gz	Fastqsanger.gz
	SRR32206232_2.fastq.gz	Fastqsanger.gz
	SRR32206233.fastq.gz	Fastqsanger.gz
	SRR32206233_1.fastq.gz	Fastqsanger.gz

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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition.

Project description:Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition.

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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [ChIP-seq]

Project description:Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [ChIP-seq]

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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [RNA-seq]

Project description:Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [RNA-seq]

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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [RNA-seq]

Project description:Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutical opportunities. Here, we identified a novel subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in female highly proliferative hormone-dependent breast cancers and impair DNA repair capacity.  Mechanistically, succinate secreted by tumor-associated PreNeu inhibit homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumoral effect of these neutrophils.

2025-03-18 | GSE288569 | GEO

Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [ChIP-seq]

2025-03-18 | GSE288568 | GEO

ID3 Promotes Homologous Recombination via Non-transcriptional and Transcriptional Mechanisms and its Loss Confers Sensitivity to PARP Inhibition

Project description:The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction of basic helix-loop-helix transcription factors with their target DNA sequences. We previously reported that ID3 loss is associated with mutational signatures linked to DNA repair defects. Here we demonstrate that ID3 exhibits a dual role to promote DNA double-strand break (DSB) repair, particularly homologous recombination (HR). ID3 interacts with the MRN complex and RECQL helicase to activate DSB repair and it facilitates RAD51 loading and downstream steps of HR. In addition, ID3 promotes the expression of HR genes in response to ionizing radiation by regulating both chromatin accessibility and activity of the transcription factor E2F1. Consistently, analyses of TCGA cancer patient data demonstrate that low ID3 expression is associated with impaired HR. The loss of ID3 leads to sensitivity of tumor cells to PARP inhibition, offering new therapeutic opportunities in ID3-deficient tumors.

2022-02-17 | PXD028946 | Pride

Amplification of mutant BRCA2 gene confers resistance to PARP inhibitor

Project description:Breast cancer gene 2 (BRCA2) deleterious mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to its critical role in DNA repair. PARP inhibitor Olaparib is now approved and several other PARP inhibitors are now in different stages of clinical trials. Development of resistance to PARP inhibitors limits their clinical utility. The mechanism of resistance remains not fully understood. Here we show that amplification of mutant BRCA2 confers PARP inhibitor resistance. The amplification of mutant BRCA2 gene copies correlates with an increase in mutant BRCA2 expression and an increase in the levels of its interacting proteins PALB2 and RAD51. In addition, homologous recombination mediated DNA repair is rescued in these cells as evidenced by the formation of RAD51 focus formation. The overexpressed mutant BRCA2 is essential for the observed PARP inhibitor resistance because knockdown of its expression is sufficient to re-sensitize these cells to PARP inhibition. Collectively, our results indicate a new mechanism of resistance to PARP inhibitor in BRCA2 mutant cancer cells

2017-09-02 | GSE86394 | GEO

b00e3b5e-e665-4933-b60b-86a095c708cb - samples

Project description:Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer. RNA-Seq data for paired baseline and end of treatment samples

| EGAD00001006120 | EGA

MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage

Project description:Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. Here we characterize C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a DNA repair factor involved in HR. MCM8IP-deficient cells exhibit HR defects, especially in long-tract gene conversion, occurring downstream of RAD51 loading, consistent with a role for MCM8IP in HR-dependent DNA synthesis. Moreover, loss of MCM8IP confers cellular sensitivity to crosslinking agents and PARP inhibition. Importantly, we report that MCM8IP directly associates with MCM8-9, a helicase complex mutated in primary ovarian insufficiency, and RPA1. We additionally show that the interactions of MCM8IP with MCM8-9 and RPA facilitate HR and promote replication fork progression and cellular viability in response to treatment with crosslinking agents. Mechanistically, MCM8IP stimulates the helicase activity of MCM8-9. Collectively, our work identifies MCM8IP as a key regulator of DNA damage-associated DNA synthesis during DNA recombination and replication.

2020-06-15 | PXD019156 | Pride

Cell-autonomous Inflammation of BRCA1-deficient Ovarian Cancers Drives Intrinsic Immunoreactivity and Immune Resistance through STING and VEGF

Project description:BRCA1 loss leads to tumor cell transcriptional reprogramming, resulting in a DNA damage-driven, mandatory cell-autonomous type I IFN inflammatory activation mediated by STING and TREX1/2. PARP inhibition augmented this immunoreactivity, creating contextual lethality to dual immune checkpoint blockade (ICB) in vivo. BRCA1-deficient tumor can escape T-cell inflammation through targeted deletion or methylation of the DNA sensing/IFN pathway genes, such as STING, IFNB1 or the chemokine CCL5. Alternatively, BRCA-mutated carcinomas retaining immunoreactivity upregulate their VEGF-A expression driven by STING, which mediates immune resistance and tumor progression. STING elimination attenuated tumor growth and abrogated therapeutic resistance to dual ICB. VEGF-A blockade synergized with immune checkpoint blockade and/or PARP inhibition to control outgrowth of Brca1-/- ovarian tumors, offering opportunities for rational combination therapy of cancers with homologous recombination repair deficiency (HRD).

2021-06-16 | GSE162935 | GEO

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