Ontology highlight
ABSTRACT:
PROVIDER: PRJNA700673 | ENA |
REPOSITORIES: ENA
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Project description:Here we found that ILF3 prefers to bind telomere R-loops and protects telomere from aberrant homologous recombination. ILF3 knockout induces TERRA aggregation onto telomere and activates telomere DNA damage response (DDR). Furthermore, ILF3 deficiency disrupts telomere homeostasis and induces abnormal ALT-mediated telomere lengthening
2022-03-04 | PXD032093 | iProX
Project description:HS-10502 is a Poly(ADP-ribose) polymerase 1 (PARP1)-specific selective inhibitor. The purpose if this study is to assess the safety, tolerability, pharmacokinetics (PK), and efficacy of HS-10502 in subjects with homologous recombination repair (HRR) gene mutant or homologous recombination deficiency (HRD) positive advanced solid tumors.
| 9330 | ecrin-mdr-crc
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
Project description:Homologous recombination deficiency (HRD) score in a large cohort of 55 triple-negative breast cancer PDX
| EGAD00001008839 | EGA
Project description:<p>Many tumors maintain chromosome ends through a telomerase-independent, homologous recombination based mechanism called alternative lengthening of telomeres (ALT). While ALT occurs in only a subset of tumors, it is strongly associated with mutations in the genes encoding components of the histone H3.3 chaperone complex, ATRX and DAXX. To date the mechanistic role of ATRX and particularly DAXX mutations in potentiating ALT remains poorly understood. We identify an osteosarcoma cell line, G292, with a unique chromosomal translocation resulting in loss of DAXX function, while retaining functional ATRX. Using this distinctive resource, we demonstrate that introduction of wild type DAXX suppresses the ALT phenotype and restores localization of the ATRX/DAXX complex to PML bodies. This provides the first direct molecular evidence that ongoing DAXX deficiency is essential for maintenance of the ALT phenotype and highlights the potential for therapeutic targeting of this oncogenic pathway.</p>
| phs001495 | dbGaP
Project description:In mammalian cells, classical non-homologous end joining (c-NHEJ) is critical for DNA double-strand break repair induced by ionizing radiation and during V(D)J recombination in developing B and T lymphocytes. Recently, PAXX was identified as a new c-NHEJ core component. We report here, that PAXX-deficient cells exhibit a cellular phenotype uncharacteristic of a deficiency in c-NHEJ core components. PAXX-deficient cells display normal sensitivity to radiomimetic drugs, are proficient in transient V(D)J recombination assays, and do not shift towards higher micro-homology usage in plasmid repair assays. Although PAXX-deficient cells lack c-NHEJ phenotypes, PAXX forms a ternary complex with Ku bound to DNA. Formation of this complex involves an interaction with Ku70 and requires a bare DNA extension for stability. Moreover, the relatively weak Ku-dependent stimulation of LIG4/XRCC4 activity by PAXX is unmasked by XLF ablation. Thus, PAXX plays an accessory role during c-NHEJ that is largely overlapping with XLF’s function.
2016-10-06 | PXD004659 | Pride
Project description:Mastl is commonly overexpressed in cancer, appearing as an alternative therapeutic anticancer target. Loss of Mastl induces multiple chromosomal mitotic errors that lead to the accumulation of micronuclei and multilobulated cells with polyploidy. Our detailed analyses display that loss of Mastl quickly lead to chromosomes breakage and abnormalities impairing correct segregation. Phosphoproteomic data of mouse embryonic fibroblasts revealed defects in kinetochores, perichromosomes, and centrosomes but also on RNA binding proteins and double strand DNA damage repair.In our study, Rad51ap1, a well-known homologous recombination regulator, appeared to be effectively phosphorylated by Nek2 and CDK1, but also efficiently depshosphorylated by PP2A/B55. Taken together, these results suggest that Mastl loss induces a multitude of alteration even in noncancerous cells that lead to the disruption of DNA damage repair triggering chromosomes breakage and in consequence, creates an accumulative disequilibrium in the phosphoproteome.
2020-10-15 | PXD019297 | JPOST Repository
Project description:Genomic instability is a hallmark of many cancers. Aberrant proliferation in cancer cells leads to the accumulation of alterations in genes that belong to the homologous recombination (HR) DNA double-strand break (DSB) repair pathway. Deficiency in HR-mediated repair (HRR) exacerbates genomic instability and correlates with poor prognosis and development of metastases. Determining HRR deficiency (HRD) in a given tumour is of major clinical relevance as it is associated with therapeutic vulnerabilities. HRD has been widely investigated in certain tumor types such as ovarian and breast cancer but remains greatly unexplored in sarcoma, a rare and heterogeneous group of mesenchymal cancer. Here, we show that specific sarcoma entities are characterized by high levels of genomic instability signatures and a wide range of molecular alterations in HRR genes, while exhibiting a complex pattern of chromosomal instability features. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signatures that predicts PARP inhibitor sensitivity in patient-derived ex vivo sarcoma models. Concomitantly, HRDhigh sarcoma cell models lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HR-mediated DNA repair. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness traits and demonstrate clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways in patient-derived ex vivo cell models and in a leiomyosarcoma patient. In summary, we provide the most comprehensive analysis of HRDness in sarcoma to date and support a bench-to-bedside personalized oncological approach to successfully treat sarcoma patients.
2023-01-18 | GSE221532 | GEO
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
Project description:A Phase 2, open-label, single-arm trial to evaluate the response of rucaparib in participants with various solid tumors and with deleterious mutations in Homologous Recombination Repair (HRR) genes.
| 2322588 | ecrin-mdr-crc