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EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

ABSTRACT: EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

PROVIDER: PRJNA739447 | ENA |

REPOSITORIES: ENA

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EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

Project description:EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

| PRJNA692239 | ENA

EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

Project description:Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are characterized by worse overall outcomes and resistance to immunotherapy. Here, we identified a molecular mechanism by which KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY producing a BRCAness phenotype characterized by HRR defects and sensitivity to PARP inhibitors (PARPis). Defective HRR increases genomic instability leading to high tumor mutational burden (TMB), which prompts an innate immune response. Notably, EMSY accumulation also suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling, impairing the growth of KEAP1-mutant tumors. Our results suggest that targeting the PARP and STING pathways, individually or in combination, represent a novel therapeutic strategy in NSCLC patients harboring alterations in KEAP1.

2022-01-04 | GSE178503 | GEO

EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion.

Project description:Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.

| S-EPMC8751279 | biostudies-literature

EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

Project description:Purpose: The goal of this study is to analyze the transcriptional pathways regulated by Emsy and Keap1 in subcutaneous mouse lung adenocarcinoma tumors. Methods: Keap1 wild type (KP) or mutant (KPK) cells expressing inducible shEmsy or shCTRL were implanted subcutaneously into the flanks of 6- to 8-week-old female syngeneic mice. Once tumors were measurable mice were treated with doxycycline to induce the shRNA expression. Knock down efficiency has been evaluated by western blot (using specific antibody for Emsy) and qPCR (using specific oligos for Emsy). Results: The transcriptomic analysis helps us to support our finding that Keap1-null tumors are characterized by suppression of the IFN response resulting from the stabilization of Emsy.

2021-01-15 | GSE164872 | GEO

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

BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair

2012-09-30 | GSE35698 | GEO

A complex of BRCA2 and PP2A-B56 is required for homologous recombination-mediated DNA repair

Project description:Mutations in the tumour suppressor BRCA2 are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination. BRCA2 acts by promoting RAD51 nucleofilament formation on resected single-stranded DNA, but how BRCA2 activity is regulated during HR is not fully understood. Here, we delineate a pathway where ATM and ATR kinases phosphorylate a highly conserved region in BRCA2 in response to DNA DSBs. These phosphorylations stimulate the binding of the protein phosphatase PP2A-B56 to BRCA2 through a conserved binding motif. We show that the phosphorylation-dependent formation of the BRCA2-PP2A-B56 complex is required for efficient RAD51 loading to sites of DNA damage and HR-mediated DNA repair. Moreover, we find that several cancer-associated mutations in BRCA2 deregulate the BRCA2-PP2A-B56 interaction and sensitize cells to PARP inhibition. Collectively, our work uncovers PP2A-B56 as a positive regulator of BRCA2 function in HR with clinical implications for BRCA2 and PP2A-B56 mutated cancers.

2021-07-26 | MSV000087884 | MassIVE

The Efficacy and Safety of Fluzoparib Plus Irinotecan as Second-line Treatment in Patients With Homologous Recombination Deficiency (HRD) Metastatic Colorectal Cancer.

Project description:Preclinical data support the investigation of PARP inhibitors in other neoplasms exhibiting homologous recombination deficiency (HRD) as monotherapy as well as in combination with chemotherapy. However，in colorectal cancer (CRC), the role of HRD alterations is mostly unknown. This study aims to explore the the Efficacy and Safety of Fluzoparib combined with Irinotecan in the Second-line treatment of HRD alterations metastatic colorectal cancer.

| 8652 | ecrin-mdr-crc

PRMT5 regulates the homologous recombination DNA repair pathway by controlling the alternative splicing of key epigenetic factors

Project description:We found that PRMT5 deletion or inhibition impairs homologous recombination (HR) DNA repair, leading to DNA damage accumulation, p53 activation, cell cycle arrest and cell death through missplicing of KAT5. We show that PRMT5 inhibitors and PARP inhibitors have synergistic effects on human acute leukemia cell lines, demonstrating the advantages of combining targeted epigenetic and non-epigenetic inhibitors.

2018-09-04 | GSE107854 | GEO

SETMAR functions in illegitimate DNA recombination and non-homologous end joining repair

Project description:SETMAR functions in illegitimate DNA recombination and non-homologous end joining repair

| PRJNA533076 | ENA